Copeland ML, Bruner JP, Richards WO, Sundell HW, Tulipan NB
Neurosurgery, 33(3):542-4;discussion 545, 1993 Sep
An animal model for intrauterine surgical treatment of myelomeningocele is described using sheep. We report the technical feasibility of endoscopic intrauterine skin graft placement over surgically induced defects, including over exposed spinal cord. These grafts exclude amniotic fluid from the underlying lesion and provide a matrix for fetal skin growth below the graft. The potential for human application is discussed.
Drewek MJ, Bruner JP, Whetsell WO, Tulipan N
Pediatric Neurosurgery, 1997; 27:190-3.
Abstract: It has been proposed that the myelodysplastic components of a myelomeningocele are secondarily damaged as the result of exposure to amniotic fluid, the so-called 'two-hit' hypothesis. The critical time at which this secondary insult might occur has not been clearly defined. The present study addresses this issue by quantitatively assessing the toxic effects of human amniotic fluid of various gestational ages upon organotypic cultures of rat spinal cord. Using an assay for lactate dehydrogenase efflux to evaluate toxicity in such spinal cord cultures, we found that the amniotic fluid became toxic at approximately 34 weeks' gestation. This toxic effect of amniotic fluid appears to emerge rather suddenly. Accordingly, it seems reasonable to suggest that prevention of exposure of vulnerable spinal cord tissue to this toxicity by surgical closure of a myelomeningocele defect prior to the emergence of toxicity in amniotic fluid may prevent injury to vulnerable myelodysplastic spinal cord tissue.
Endoscopic coverage of fetal open myelomeningocele in utero
Bruner JP, Tulipan NB, Richards WO
American Journal of Obstetrics & Gynecology. 176(1 Pt 1);256-7, 1997 Jan. [letter; comment]
Endoscopic coverage of fetal myelomeningocele in utero*
Bruner JP, Richards WO, Tulipan NB, Arney TL
American Journal of Obstetrics & Gynecology, 176, 1997 Jan.
Objective: Evaluate the safety and efficacy of minimally invasive surgery for the coverage of myelomeningocele in utero.
Study Design: Women in the mid-second trimester of a pregnancy complicated by fetal myelomeningocele were offered an experimental procedure designed to prevent ongoing exposure of the spinal cord to the intrauterine environment. The procedure consisted of maternal laparotomy under both general and epidural anesthesia, with exposure of the gravid uterus. Endoscopic ports were placed for camera and operating instruments. Amniotic fluid was removed and replaced with carbon dioxide. The fetus was then positioned and a maternal split-thickness skin graft was placed over the exposed spinal cord or neural elements. The skin graft and a covering of Surgicel™ were attached with fibrin glue prepared from autologous cryoprecipitate.
Results: Four fetuses with open myelomeningocele underwent endoscopic coverage of the spinal lesion at a mean gestational age of 23 1/7 wks (±1 0/7 wks, SD). One infant, delivered by planned cesarean section at 35 weeks' gestation after demonstration of fetal lung maturity, is almost three years old. A second infant was delivered by cesarean section at 28 weeks after preterm labor, and is now almost six months old. Both survivors manifest only mild motor and somatosensory deficits. One fetus was delivered one week postoperatively after development of amnionitis, and expired in the delivery room from extreme prematurity. The final fetus died intraoperatively from placental abruption.
Conclusion: Minimally invasive fetal surgery appears to constitute a feasible approach to nonlethal fetal malformations that result in progressive and disabling organ damage.
*Endoscopic surgery to repair spina bifida in utero is no longer being performed at Vanderbilt University Medical Center, or anywhere else. After completing the four cases listed above, it became obvious that definitive repair of the spina bifida defect through an open incision was technically possible, and offered the opportunity for an improved outcome. Early in 1997, we developed the open fetal approach to spina bifida repair which has now become the standard for this procedure.
Tulipan N, Bruner JP
Pediatric Neurosurgery, 1998;28:177-180
Background: Evidence accumulating over the last ten years suggests that the exposed spinal cord tissue in a myelomeningocele sustains a secondary injury as the result of prolonged exposure to the intrauterine environment. These data suggest that early closure of the myelomeningocele sac might prevent such injury, and in turn improve outcome in the affected infant.
Methods: Three patients with fetuses carrying the ultrasonic diagnosis of myelomeningocele elected to enter a study of the feasibility of repairing myelomeningocele in utero. At approximately 28 weeks of gestation each patient underwent laparotomy and hy7steroltomy, thus exposing the myelomeningocele defect. The defect was closed in routine surgical fashion, and the hysterotomy then closed.
Results: The three patients recovered from surgery without incident. Early premature contractions subsided, and they were discharged by the 5th postoperative day. At between 33 and 36 weeks of gestation each infant was delivered via cesarean section. The observed neurologic deficits were within the range expected from the anatomic level of the defects. Two of the infants have not required ventriculoperitoneal shunting.
Conclusions: This limited series of patients suggests that myelomeningocele can be repaired in utero with minimal morbidity to either the mother or her fetus. A larger study will be needed to substantiate this low morbidity, and to determine the extent of any neurologic benefit of early surgery.
Bruner JP, Tulipan NB, Richards WO, Walsh WF, Boehm FH, Vrabcak EK
(Fetal Diagn Ther 15: 83-88, 2000)
Objective: To compare endoscopic coverage of myelomeningocele with a maternal split-thickness skin graft in utero to definitive neurosurgical closure through a hysterotomy.
Study Design: Four fetuses with isolated myelomeningocele underwent endoscopic coverage of the defect with a maternal split-thickness skin graft in a CO2 environment at 22-24 weeks' gestation. Subsequently, four fetuses underwent standard neurosurgical closure of their myelomeningoceles at 28-29 weeks' gestation.
Results: The mean operating time for the endoscopic procedures was 297± 69 min. Two fetal losses occurred as a result of chorioamnionitis and placental abruption, respectively. A third baby delivered at 28 weeks' gestation after prolonged disruption of the membranes. The two survivors required standard closure of the myelomeningocele after delivery. The mean operating time for the hysterotomy procedures was 125 ± 8 min. No mortality occurred, and all the infants delivered between 33 and 36 weeks with well-healed myelomeningocele scars.
Conclusions: With current technology, in utero repair of congenital myelomeningocele through a hysterotomy appears to be superior to procedures performed endoscopically.
Tulipan NT, Hernanz-Schulman M, Bruner JP
(Pediatr Neurosurg1998; 29: 274-8)
Background: It has been theorized that fetal myelomeningocele repair may reduce ongoing intrauterine injury and perhaps allow healing and regeneration of dysplastic neural tissue. We report on the postnatal imaging studies of the first 4 patients to have undergone intrauterine myelomeningocele repair at our institution.
Methods: Each of the 4 patients underwent postnatal sonographic and MRI imaging. In addition, the postnatal ultrasounds of these 4 were compared to a group of retrospective controls.
Results: MRI scans of the four experimental subjects revealed no evidence of hindbrain herniation while other stigmata of the Chiari II malformation persisted. In comparison to the retrospective controls this absence of herniation was distinctly unusual.
Conclusion: Intrauterine myelomeningocele repair may reduce the degree of hindbrain herniation normally seen in patients with myelomeningocele. This raises the possibility that intrauterine repair may decrease the morbidity associated with the Chiari type II malformation including dysfunction, hydrocephalus and syringomyelia.
Intrauterine myelomeningocele repair reverses preexisting hindbrain herniation
Tulipan N, Hernanz-Schulman M, Bruner JP
Pediatr Neurosurg 1999 Sep;31(3):137-42
Background: It has been reported that intrauterine myelomeningocele repair reduces the amount of hindbrain herniation normally seen in association with the Chiari type II malformation. It is not yet known, however, whether hindbrain herniation is prevented, or whether preexisting herniation is reversed. The following study was designed to elucidate this issue.
Methods: A series of 9 patients underwent intraoperative ultrasound examinations immediately prior to intrauterine myelomeningocele repair. These same patients were then evaluated postnatally using ultrasound and/or MRI. The degree of hindbrain herniation before and after repair was compared using a grading system devised by the authors.
Results: Eight patients had clear evidence of moderate to severe hindbrain herniation on intraoperative scans while one was mild. In contrast, on postnatal studies 5 of 9 patients had no evidence of hindbrain herniation, while the other 4 had only mild herniation.
Conclusion: Intra-uterine myelomeningocele repair appears to reverse preexisting hindbrain herniation. It is postulated that continuous flow of cerebrospinal fluid through the neural placode is the force responsible for inducing migration of the cerebellum and brain stem downward through the foramen magnum. By interrupting that flow during gestation, intrauterine myelomeningocele repair enables the cerebellum and brain stem to resume a normal, or nearly normal, configuration.
Fetal Surgery for Myelomeningocele and the Incidence of Shunt-Dependent Hydrocephalus
Joseph P. Bruner, MD; Noel Tulipan, MD; Ray L. Paschall, MD; Frank H. Boehm, MD; William F. Walsh, MD; Sandra R. Silva, MD; Marta Hernanz-Schulman, MD; Lisa H. Lowe, MD; George W. Reed, PhD
Tulipan NT, Bruner JP, Hernanz-Schulman M, Lowe LH, Walsh WF, Nickolaus D; Oakes WJ
Pediatr Neurosurg 1999 Oct; 31 (4):183-8
Background: It has been postulated that intrauterine myelomeningocele repair might improve neurologic outcome in patients with myelomeningocele. A total of 59 such procedures have been performed at Vanderbilt University. Preliminary results suggested that the degree of hindbrain herniation is reduced by intrauterine repair. In an attempt to further quantify the possible benefits of this surgery, a subset of these patients was brought back to Vanderbilt for study.
Methods: A group of 26 patients who had undergone intrauterine myelomeningocele repair underwent an extensive evaluation which included manual muscle testing, MR imaging and precise determination of the anatomic level of their lesions as well as multiple other tests. The results of this analysis were compared to those in 2 groups of historical controls.
Results: In this group of patients intrauterine myelomeningocele repair substantially reduced the incidence of moderate to severe hindbrain herniation (4 vs. 50%). The incidence of shunt-dependent hydrocephalus was more modestly reduced (58 vs. 92%). The average level of leg function closely matched the average anatomic level of the lesion in both the fetal surgery and control groups.
Conclusion: The most dramatic effect of intrauterine repair appears to be on hindbrain herniation. A less dramatic, but significant, reduction in shunt-dependent hydrocephalus is also seen. Prospective patients should be cautioned not to expect improvement in leg function as the result of this surgery. The potential benefits of surgery must be carefully weighed against the potential risks of prematurity.
Clinical Ethics and Fetal Surgery: Are We Ready?
Bliton MJ, and Zaner RM
(submitted for publication)
Abstract: To establish and assess the ethical issues inherent in in utero surgical interventions to repair fetal myelomeningocele, ethics consultants were involved to review and, where necessary, revise traditional informed consent; to counsel and assist understanding by participating pregnant women and spouses regarding the protocol; and to be involved in the formal institutional review and evaluation of the protocol and each participating woman and/or couple. As a result of intensive conversations with both research participants and members of the multidisciplinary team, three significant ethical questions were identified as requiring special attention and deliberation. The involvement of ethics consultants to ensure attention to the complex questions raised by these three issues is vital for providing attention to the complex questions raised by these three issues is vital for providing participants the time necessary for deliberation to ensure genuine understanding and choice, and therefore informed consent--here conceptualized as a process.
Use of bipedicular advancement flaps for intrauterine closure of myeloschisis
Magels KJ, Tulipan N, Bruner JP, Nickolaus D
Pediatr Neurosurg 2000 Jan;32(1):52-6
Abstract: Several groups have begun to explore the feasibility and utility of intrauterine closure of myelomeningocele. A subset of these fetuses have defects which fall into the category of myeloschisis, and therefore have inadequate skin to enable primary closure. After considerable discussion, it was decided to utilize bipedicular flaps to close these lesions. The procedure is described, and representative samples have been shown. To date 13 or 56 fetuses have required this approach for closure in utero. while this technique generally provides adequate coverage of the dural sac, the cosmetic results have been less than optimal.
The urodynamic profile of myelodysplastic children with spinal closure in utero
Holzbeierlein, J, Pope JC, Adams MC, Bruner JP, Tulipan N, Brock JW
(submitted for publication)
Background: Spinal dysraphism is the most common cause of neurogenic bladder dysfunction in newborns. Urodynamic findings in these children include uninhibited bladder contractions, bladder areflexia, decreased compliance, and detrusor sphincter dyssynergia. Early urodynamic studies in patients with spina bifida is recommended to help identify those with bladder characteristics that place them at risk for upper tract deterioration. A new intervention employing closure of the neural tube defect in utero has recently been investigated at our institution in 25 patients. The supposition is that this procedure produces decreased exposure of the spinal cord to the amniotic fluid, which may improve neurologic function. To date, we have studied 16 of these patients with video urodynamics and compared the results to those reported in the literature on myelomeningocele patients without fetal intervention.
Methods: Sixteen patients with a mean age of 6.5 months (range 2-12 months) have undergone urodynamic testing including cystometrogram, fluoroscopic evaluation of filling and voiding, electromyographic studies of the pelvic floor and measurement of post void residual. In addition, renal ultrasounds, voiding cystourethrograms, the need for catheterization, the number of urinary tract infections, and medications were reviewed.
Results: Six percent of these patients demonstrated uninhibited detrusor contractions while 43% had an areflexic bladder. Nineteen percent demonstrated decreased compliance, and 75% had leak point pressures greater than 40 cm of H2O. Mean bladder capacity was 40 cc with 31% of patients having a much lower capacity than expected for age. Two patients had evidence of upper tract dilation on previous renal ultrasounds; 2 had evidence of reflux on VCUG; 2 required intermittent catheterization; 1 required anticholinergic therapy; and 1 patient experienced a significant urinary tract infection.
Conclusion: The urodynamic findings in this population are comparable to those previously reported in the literature for patients with spina bifida without prenatal closure of the spinal defect. Our lower incidence of urinary tract infections and reflux probably represents more aggressive early urologic management of these patients rather than neurologic improvement. These urodynamic studies were performed very early in life and future evaluations may ultimately reveal improvement in bladder function when compared to other myelodysplastic patients. At this time, however, we recommend that patients with in utero closure of their spinal cord defect be evaluated and treated in the same manner as myelomeningocele patients without fetal intervention.
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