Tethering of the spinal cord in mouse fetuses and neonates with spina bifida

Stiefel, Dorothea; Sawada, Takashi; Meuli, Martin; Duffy, P.G.; Copp, Andrew J.

doi:10.3171/spi.2003.99.2.0206

Cited by 25 publications

(23 citation statements)

References 34 publications

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“…23,24,28,29 Our study is the first in which fetuses of mutant ct/lp mice have been used to evaluate the changes that occur in vascular structure and apoptosis in the placode of MMC mice during in utero development. To make such determinations, we used immunocytochemical labeling of endothelial and apoptotic cells of MMC placodes of fetuses at embryonic Days 14.5 to 18.5.…”

Section: Discussionmentioning

confidence: 99%

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Vascular and apoptotic changes in the placode of myelomeningocele mice during the final stages of in utero development

Reis

Correia‐Pinto

Monteiro

et al. 2008

PED

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Object Myelomeningocele (MMC) is a primary neurulation defect that is associated with devastating neurological disabilities in affected newborns. To better characterize the in utero neurodegenerative process of MMC, the authors investigated the changes in vascular organization, apoptosis, and the presence of inflammatory cells during gestation by using a mutant mouse model of MMC. Methods The curly tail/loop tail (ct/lp) mutant mouse model of MMC was chosen to obtain fetuses at different stages of gestation. Mouse fetuses harboring MMC were harvested by caesarean section at embryonic Days 14.5, 16.5, and 18.5 (complete mouse gestation at 19 days, 6 mice/group); littermate fetuses with the same gestational age but without an MMC were used as controls. Samples of the MMC placode or normal spinal cord were stained for immunocytochemical labeling with caveolin antibody (endothelium marker) and activated caspase-3 antibody (apoptosis marker). Samples were morphometrically analyzed with a computer-assisted image analyzer. Results The MMC mice presented with an increase in vascular density from embryonic Days 16.5–18.5 and an enhanced number of apoptotic cells at embryonic Day 18.5, compared with controls. There were scarce signals of an inflammatory reaction in the MMC placode, as a few infiltrating neutrophils were seen only at embryonic Day 18.5. Conclusions Fetal placodes in MMC mice showed evidence of increased vascular density since embryonic Day 16.5 and increased apoptosis at embryonic Day 18.5. These new data support the view that in utero changes of the MMC placode, occurring during the last stages of gestation, contribute to the neuropathological manifestations in full-term newborns with MMC.

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Section: Discussionmentioning

confidence: 99%

“…Mice harboring both curly tail and loop-tail mutations (ct/ct, lp/+) are known to express severe MMC almost invariabily. 29 …”

Section: Mouse Strains and Breedingmentioning

confidence: 99%

Vascular and apoptotic changes in the placode of myelomeningocele mice during the final stages of in utero development

Reis

Correia‐Pinto

Monteiro

et al. 2008

PED

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“…42 The mouse mutant expressing the ct mutation was purchased from the Jackson Laboratory and the lp mutation mouse was offered to us by Dr. Andrew Copp (Neural Development Unit, Institute of Child Health, University College London). The mice were housed in a controlled temperature room that was maintained with a 12-hour light/dark cycle.…”

Section: Animal Model and Experimental Designmentioning

confidence: 99%

“…The ct/lp model of MMC has been used before 42 and was chosen to characterize the topographical changes that occur in the placode during gestation. These alterations were defined through a morphometric analysis of immunostained glial and neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

In utero topographic analysis of astrocytes and neuronal cells in the spinal cord of mutant mice with myelomeningocele

Reis¹,

Correia‐Pinto²,

Monteiro³

et al. 2007

Journal of Neurosurgery: Pediatrics

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Object Myelomeningocele (MMC) is the most severe form of spina bifida causing severe neurological deficits. Injury to the placode has been attributed to in utero aggression. In this study, glial and neuronal cell changes in both number and topography in mice with MMC were investigated during gestation. MethodsThe curly tail/looptail mice model of MMC was used, and fetuses were harvested using caesarean surgery at Days 14.5, 16.5, and 18.5 (full gestation at 19 days). Immunohistochemical analyses of the MMC placodes and the normal spinal cords from the control group were performed using anti-glial fibrillary acidic protein (astrocytes) and mouse anti-neuronal nuclear (neurons) antibodies. Light microscopy was used along with computer-assisted morphometric evaluation.Progressive increases in astrocytes in the spinal cord of all mouse fetuses were found between Days 14.5 and 18.5 of gestation. This increase was significantly higher in the placodes of mice with MMC than in those of normal mice, particularly in the posterior region. Neuronal labeling at Day 14.5 of gestation was similar between mice with MMC and control mice. At Day 16.5 of gestation there was a deterioration of neural tissue in MMC fetuses, mainly in the posterior region, progressing until the end of gestation with a marked loss of neurons in the entire MMC placode. ConclusionsThis study delineated the quantitative changes in astrocytes and neurons associated with MMC development during the late stages of gestation. The detailed topographic analysis of the MMC defines the timing of the intrauterine insult and how the placode lesions progress. This study supports the current concept of placode protection through in utero surgery for fetuses with MMC.KEYWORDS:myelomeningocele; astrocyte; neuronal cell; immunohistochemistry; fetal surgery; pediatric neurosurgery. IntroductionSpina bifida aperta, or MMC, is a primary neurulation defect that is associated with a significant morbidity and mortality rate in the affected children. 6 , 12 , 15 , 34 Myelomeningocele occurs in nearly 1 in every 2000 live births, 29 , 44 even in countries where maternal folic acid supplementation and an early in utero diagnosis of MMC is available. 6 , 34 , 35 Myelomeningocele leads to lifelong and devastating physical disability; MMC newborns present with different degrees of lower extremity paralysis, sexual organ and sphincter dysfunction, tethering of the spinal cord, skeletal abnormalities, brainstem dysfunction, and hydrocephalus, and may develop disorders that require the insertion of ventriculoperitoneal shunts. 3 , 34 , 38 , 43 The mortality rate in children with MMC ranges from 14 to 35% until they reach the age of 5 years. 16 , 34 , 44 , 45 The precise cause of spina bifida is unknown, and is probably of a multifactorial nature. 12 , 33 Data from the experimental induction of MMC in animal models have raised questions about the previously dominant concept of an intrinsic embryonic error causing MMC neurological deficits, 14 , 22 , 27 , 31-33 Go to ...

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“…SBA may lead to progressive complications after birth, mainly due to CM, severe hydrocephalus requiring shunting and leading to cognitive impairments namely learning disabilities, and sensorimotor deficits [11]. Tethered spinal cord syndrome is mainly a complication at the site of the repair, which can cause progressive deficits and require untethering [11,13]. CM remains the leading cause of death within the first 5 years of life due to hindbrain dysfunction developing in 17% of SBA cases [14].…”

Section: Introductionmentioning

confidence: 99%

Fetoscopic versus Open Repair for Spina Bifida Aperta: A Systematic Review of Outcomes

Joyeux

Engels²,

Russo³

et al. 2016

Fetal Diagn Ther

165

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Objective: To compare outcomes of fetoscopic spina bifida aperta repair (FSBAR) with the results of the open approach (OSBAR) as in the Management Of Myelomeningocele Study (MOMS). Methods: This was a systematic comparison of reports on FSBAR with data from the MOMS (n = 78). Inclusion criteria were studies of spina bifida aperta patients who underwent FSBAR and were followed for ≥12 months. Primary outcome was perinatal mortality. Secondary outcomes included operative, maternal, fetal, neonatal and infant outcomes. Results: Out of 16 reports, we included 5 from 2 centers. Due to bias and heterogeneity, analysis was restricted to two overlapping case series (n = 51 and 71). In those, FSBAR was technically different from OSBAR, had comparable perinatal mortality (7.8 vs. 2.6%, p = 0.212) and shunt rate at 12 months (45 vs. 40%, p = 0.619), longer operation time (223 vs. 105 min, p < 0.001), higher preterm prelabor membrane rupture rate (84 vs. 46%, p < 0.001), earlier gestational age at birth (32.9 vs. 34.1 weeks, p = 0.03), higher postnatal reoperation rate (28 vs. 2.56%, p < 0.001) and absence of uterine thinning or dehiscence (0 vs. 36%, p < 0.001). Functional outcomes were not available. Conclusion: FSBAR utilizes a different neurosurgical technique, takes longer to complete, induces more prematurity, requires additional postnatal procedures, yet has a comparable shunt rate and is not associated with uterine thinning or dehiscence. Long-term functional data are awaited.

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Tethering of the spinal cord in mouse fetuses and neonates with spina bifida

Cited by 25 publications

References 34 publications

Vascular and apoptotic changes in the placode of myelomeningocele mice during the final stages of in utero development

Vascular and apoptotic changes in the placode of myelomeningocele mice during the final stages of in utero development

In utero topographic analysis of astrocytes and neuronal cells in the spinal cord of mutant mice with myelomeningocele

Fetoscopic versus Open Repair for Spina Bifida Aperta: A Systematic Review of Outcomes

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