Enrico Danzer

Retinoic acid induced myelomeningocele in fetal rats: characterization by histopathological analysis and magnetic resonance imaging.

The prevention of human neural tube defects by folic acid administration and the potential for fetal surgical intervention for myelomeningocele (MMC) have renewed interest in the molecular pathways and pathophysiology of spina bifida. Animal models for assessment of the early developmental biology and pathophysiology of this lesion are needed. The goal of this study was to develop and characterize a non-surgical rat model of MMC. Time-dated Sprague-Dawley rats were gavage fed different doses of retinoic acid (RA) dissolved in olive oil at E10 (maternal n = 55, fetal n = 505). Control animals received olive oil alone (maternal n = 20, fetal n = 265) or were untreated (maternal n = 5, fetal n = 63). Fetuses were analyzed by detailed histopathology and MRI. Overall, isolated MMC occurred in 60.7% (307/505) of RA-exposed fetuses and no controls. Histopathology confirmed the entire spectrum of severity observed in human MMC, ranging from exposure of the cord with intact neural elements to complete cord destruction. MRI of the brain of MMC fetuses confirmed structural changes similar to humans with Arnold-Chiari malformation, including downward displacement of the cerebellum to just above the foramen magnum and compression of the developing medulla into a small posterior fossa. In conclusion, the RA-induced rat model of MMC is developmentally and anatomically analogous to human MMC. This relatively efficient and cost-effective model of MMC should facilitate investigation of the developmental biology and pathophysiology of MMC, and may be useful for the evaluation of further strategies for prenatal treatment.

Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program.

PURPOSE The purpose of the study was to evaluate the neurodevelopmental outcome in infants with congenital diaphragmatic hernia (CDH). METHODS Between June 2004 and September 2007, 41 CDH survivors were prospectively enrolled in an interdisciplinary follow-up program. Neurodevelopmental status was evaluated using the Bayley Scales of Infant Development II (prior 2006, n = 9), the Bayley Scales of Infant Development III (after 2006, n = 27), or the Wechsler Preschool and Primary Scale of Intelligence III (children older than 4 years, n = 5). Scores were grouped as average, mildly delayed, and severely delayed by standard deviation intervals (115-85, 71-84, <70), and mixed if average and mildly delayed in either cognitive or language. RESULTS Median age at last assessment was 24 months (range, 6-62). Average, mixed, mildly delayed, and severely delayed scores for neurocognitive and language skills were found in 49%, 19%, 17%, and 15%, respectively. Psychomotor scores were normal, mildly delayed, and severely delayed in 46%, 23%, and 31%, respectively. Autism was present in 7%. Abnormal muscle tonicity was found in 51% (49% hypotonic, 2% hypertonic). Multivariate risk factors for borderline or delayed neurodevelopmental, neurocognitive, and/or psychomotor outcome were intrathoracic liver position (P = .02), presence of a right-sided CDH (P = .02), extracorporeal membrane oxygenation need (P < .001), Gore-Tex patch repair (P = .02), O(2) requirement at 30 days of life (P < .01), and hypotonicity (P < .01). CONCLUSIONS The prospective evaluation in an interdisciplinary follow-up program uncovered striking morbidities in neurodevelopmental status in approximately half of the CDH infants. The most common neurologic sequelae are neuromuscular hypotonicity and psychomotor dysfunction. Patient-specific factors are important determinants of adverse neurologic outcome.

Lower Extremity Neuromotor Function and Short-Term Ambulatory Potential following in utero Myelomeningocele Surgery

Objective: To evaluate lower extremity neuromotor function (LENF) and short-term ambulatory potential following fetal myelomeningocele (fMMC) closure. Methods: Retrospective chart review of 54 children that underwent fMMC closure at our institution prior to the NIHCD-MOMS trial. Neonatal LENF was compared to predicted function based on spinal lesion level assigned by prenatal ultrasound. Ambulatory status was classified as independent walkers (walks without assistive appliances), assisted walker (requires walking aid), and non-ambulatory (wheelchair bound). Results: Thoracic, lumbar, and sacral level lesions were present in 4, 44 and 6 fMMC infants, respectively. 31/54 of fMMC children (57.4%; median: 2 levels, range: 1–5) had better than predicted, 13/54 (24.1%) same as predicted and 10/54 (18.5%; median: 1 level, range: 1–2) worse than predicted LENF at birth. At a median follow-up age of 66 months (36–113), 37/54 (69%) walk independently, 13/54 (24%) are assisted walkers, and 4/54 (7%) are wheelchair dependent. The strongest factors predicting a lower likelihood to walk independently were higher-level lesion (>L4, p = 0.001) and the development of clubfoot deformity after fetal intervention (p = 0.026). Despite the observed improved ambulatory status, structured evaluation of coordinative skills revealed that the majority of independent ambulators and all children that require assistive devices to walk experience significant deficits in lower extremity coordination. Conclusions: We observed that fMMC surgery in this highly selective population results in better than predicted LENF at birth and short-term ambulatory status. However, fMMC toddlers continue to demonstrate deficits in movement coordination that are characteristic for children with spina bifida.

Radiofrequency ablation vs bipolar umbilical cord coagulation in the management of complicated monochorionic pregnancies

The application of radiofrequency ablation (RFA) termination procedures to complicated cases involving monochorionic twins offers the potential of a less invasive option when compared to endoscopic techniques. The purpose of this study was to compare outcomes between these two techniques.

Use of magnetic resonance imaging in prenatal prognosis of the fetus with isolated left congenital diaphragmatic hernia.

To investigate the prognostic value of magnetic resonance‐calculated fetal lung volumes (FLV) in fetuses with isolated left congenital diaphragmatic hernia (L‐CDH) who receive standardized prenatal and postnatal care at a single institution.

Reversal of Hindbrain Herniation after Maternal-fetal Surgery for Myelomeningocele Subsequently Impacts on Brain Stem Function

The aim of our study was to delineate whether the reversal of hindbrain herniation (HH) following fetal myelomeningocele (fMMC) closure subsequently reduces the incidence and severity of HH-associated brainstem dysfunction (BSD). Prior to the NIH-sponsored Management of Myelomeningocele Study (MOMS) trial, 54 children underwent fMMC closure at our institution. Forty-eight (89%) families participated in a structured survey focusing on HH-associated BSD (e.g., apnea, neurogenic dysphagia [ND], gastro-esophageal reflux disease [GERD], neuro-ophthalmologic disturbances [NOD]). Median age at follow-up was 72 months (range: 46-98). Fifty-percent required shunting. HH-related symptoms were completely absent in 15 (63%) non-shunted and 10 (42%) shunted children (P=0.15). No HH-related death occurred and none developed severe persistent cyanotic apnea. ND was reported in 2 (8%) non-shunted and 9 (38%) shunted infants (P=0.03). Mild GERD (medically managed) developed in 2 (8%) without and 6 (25%) with shunt placement (P=0.24). NOD was found in 6 (25%) and 13 (54%) of non-shunted and shunted children, respectively (P=0.07). The majority of fMMC children developed no or only mild BSD at follow-up. Our data support the hypothesis that neurodevelopmental deficits associated with MMC are at least partially acquired and that reversal of HH following fMMC surgery may help to reduce the incidence and severity of BSD.

Prenatal ultrasonographic gastrointestinal abnormalities in fetuses with gastroschisis do not correlate with postnatal outcomes

PURPOSE In the setting of gastroschisis, the clinical significance of prenatal ultrasound findings of secondary changes in bowel appearance remains unknown. The purpose of this study was to correlate prenatal identification of additional gastrointestinal sonographic abnormalities with postnatal clinical outcome. METHODS A retrospective review was conducted on 64 fetuses with a prenatal diagnosis of gastroschisis treated at the Childrens Hospital of Philadelphia from 2000 to 2007. Postnatal outcomes were compared between newborns with additional sonographic gastrointestinal abnormalities and those without secondary changes to the bowel appearance. RESULTS Thirty (47%) patients had at least one gastrointestinal abnormality (eg, bowel dilatation, echogenic bowel, thickened bowel, matted bowel, herniation of the stomach through the abdominal wall defect, or segmental loss of bowel peristalsis) on prenatal ultrasound. There were no significant differences between groups with respect to the time to initial and full enteral nutrition, total hospital stay, requirement for ventilator support, central line infection rates, reoperation rates, or mortality. CONCLUSIONS In the setting of gastroschisis, isolated findings of gastrointestinal abnormalities on prenatal ultrasound do not correlate with adverse postnatal outcome.

Comparison of ultrasound and magnetic resonance imaging parameters in predicting survival in isolated left‐sided congenital diaphragmatic hernia

To compare test characteristics of ultrasound‐ and magnetic resonance imaging (MRI)‐derived parameters in predicting newborn survival in cases of isolated left‐sided congenital diaphragmatic hernia (CDH).

Amniotic fluid levels of glial fibrillary acidic protein in fetal rats with retinoic acid induced myelomeningocele: a potential marker for spinal cord injury.

OBJECTIVE The objective of this study was to determine whether amniotic fluid levels of glial acidic fibrillary protein (GFAP) would reflect myelomeningocele-related neurodegeneration in the rat model of retinoic acid-induced myelomeningocele, which is a model that is very similar to human myelomeningocele and develops the entire spectrum of disease severity including features of the Chiari II malformation. STUDY DESIGN Time-dated (embryonic day 10) pregnant Sprague-Dawley rats were gavage fed 60 mg/kg/bodyweight retinoic acid that had been dissolved in olive oil or olive oil alone. Myelomeningocele, retinoic acid-exposed no myelomeningocele, and control fetuses were harvested at specific time points throughout gestation. A standard set of pinching tests was performed to interrogate the sensorimotor reflex arc of hindpaws and tails. Amniotic fluid-GFAP levels were analyzed by standard enzyme-linked immunosorbent assay techniques. RESULTS Amniotic fluid-GFAP levels were similar between groups at embryonic days 14, 16, and 18, respectively. Compared with control fetuses, amniotic fluid GFAP levels were significantly increased in myelomeningocele fetuses at embryonic days 20 and 22 (P < .001). Defect size (P < .001), presence of clubfoot deformity (P = .0004), and absence of sensorimotor function (P < .01) at embryonic day 22 correlated with amniotic fluid-GFAP levels. CONCLUSION Amniotic fluid-GFAP levels appear to correlate with spinal cord injury as gestation proceeds in fetal rats with myelomeningocele.

Preschool neurodevelopmental outcome of children following fetal myelomeningocele closure.

OBJECTIVE We sought to investigate the preschool neurodevelopmental outcomes of children following fetal myelomeningocele (fMMC) surgery. STUDY DESIGN Prior to the Management of Myelomeningocele Study trial, 54 children underwent fMMC closure at our institution. Thirty (56%) returned at 5 years of age for standardized neurocognitive examination. Scores were grouped as high-average, average, mildly delayed, and severely delayed by SD intervals. RESULTS Mean verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), and full intelligence quotient (FIQ) scores were within normal population range. High-average or average scores for VIQ, PIQ, FIQ, and processing speed were found in 93%, 90%, 90%, and 60%, respectively. Mean FIQ and processing speed of nonshunted children were significantly higher than for those who required shunt placement (P=.02 and P=.01, respectively). Mean VIQ and PIQ tended to be higher in nonshunted fMMC children (P=.05). CONCLUSION The majority of fMMC children in this highly selective population had average preschool neurodevelopmental scores. fMMC children who did not require shunt placement were more likely to have better scores.