Sutton LN, Adzick NS, Bilaniuk LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in Hindbrain Herniation Demonstrated by Serial Fetal Magnetic Resonance Imaging Following Fetal Surgery for Myelomeningocele. JAMA. 1999;282(19):1826-1831. doi:10.1001/jama.282.19.1826
Author Affiliations: Divisions of Neurosurgery (Dr Sutton) and Pediatric General and Thoracic Surgery (Drs Adzick, Crombleholme, and Flake), Center for Fetal Diagnosis and Treatment (Drs Adzick, Crombleholme, Flake, Sutton, and Johnson), and Neuroradiology Section (Dr Bilaniuk), Children's Hospital of Philadelphia, Philadelphia, Pa; and Departments of Neurosurgery (Dr Sutton), Surgery (Drs Adzick, Crombleholme, and Flake), Radiology (Dr Bilaniuk), and Obstetrics and Gynecology (Dr Johnson), University of Pennsylvannia School of Medicine, Philadelphia.
Context Hindbrain herniation occurs in a large percentage of children with myelomeningocele
and is the leading cause of death in this population. The effect of early
fetal closure of myelomeningocele on hindbrain herniation is unknown.
Objective To determine whether early fetal closure of myelomeningocele affects
Design Case series of patients undergoing fetal myelomeningocele closure with
serial measurements of hindbrain herniation and a mean follow-up of 182 days.
Setting Tertiary care medical center.
Participants Ten patients undergoing fetal myelomeningocele closure at 22 to 25 weeks'
gestation between March 1998 and February 1999.
Main Outcome Measures Need for shunt placement; degree of hindbrain herniation (grades 0-3)
found on magnetic resonance imaging (MRI) performed prior to surgery and 3
and 6 weeks after fetal surgery, as well as shortly after birth; gestational
age at delivery.
Results All initial fetal MRI scans performed at 19 to 24 weeks' gestation showed
significant (grade 3) cerebellar herniation and absence of spinal fluid spaces
around the cerebellum. Six fetuses were delivered electively at 36 weeks'
gestation after lung maturity was established. The other 4 were delivered
prematurely, at 25, 30, 30, and 31 weeks of gestation, and the 25-week gestation
neonate died. All 9 surviving neonates showed improvement in the hindbrain
hernia at the 3-week postoperative fetal scan (grade 2, n = 4; grade 1, n
= 5). On the postnatal scan, all patients showed grade 1 hindbrain herniation.
Only 1 patient required placement of a ventriculoperitoneal shunt.
Conclusion In this series of patients, fetal myelomeningocele closure resulted
in improvement in hindbrain herniation as demonstrated by serial MRI scans.
Myelomeningocele is the most common severe birth defect involving the
central nervous system, occurring with an incidence of 4.5 per 10,000 live
births.1 The fetal prevalence is undoubtedly
higher, since myelomeningocele is frequently detected by screening amniocentesis
and ultrasound, and parents often elect to terminate the pregnancy. In addition
to spinal cord dysfunction, children with spina bifida almost invariably have
an associated Chiari II hindbrain malformation, consisting of a small posterior
fossa and downward displacement of the cerebellar vermis below the foramen
magnum into the cervical spinal canal with elongation of the brainstem and
obliteration of the fourth ventricle.2 Approximately
20% of myelodysplastic children develop symptoms of hindbrain, cranial nerve,
and spinal cord compression, usually before age 3 months. This is the principal
cause of death in this population.3,4
In addition, hindbrain herniation with obstruction of the outflow of cerebrospinal
fluid (CSF) from the fourth ventricle is believed to be the cause of hydrocephalus,
which is present in 85% of individuals with myelomeningocele.5
In the past, it was believed that the hindbrain herniation that accompanies
myelomeningocele was part of an overall cerebrospinal dysgenesis, but there
is experimental2 and clinical6- 8
evidence that both hindbrain herniation and hydrocephalus are acquired early
in fetal life and progress in severity before birth.
Fetal surgery for myelomeningocele was first attempted in the human
to prevent secondary damage to the exposed spinal cord by amniotic fluid and
mechanical trauma.9- 11
The hypothesis in undertaking correction in utero was that the lower extremity
and sphincter function at birth would be better than that expected based on
the anatomic level of the dysraphic defect. However, in our initial case,9 we noted apparent improvement in hindbrain herniation,
and, in a series of 4 patients who underwent intrauterine closure, ultrasound
images obtained after birth showed a lower than expected incidence of hindbrain
herniation.12 We report our experience with
10 patients who underwent myelomeningocele closure at 22 to 25 weeks of gestation
and were observed by means of fetal and postnatal magnetic resonance imaging
(MRI) to determine the course of hydrocephalus and hindbrain anomalies.
Beginning in 1997, expectant mothers carrying a fetus diagnosed as having
myelomeningocele were offered an intensive evaluation at the Center for Fetal
Diagnosis and Treatment at the Children's Hospital of Philadelphia and consideration
for fetal surgery. Evaluation consisted of careful review of maternal family
and medical history and records of the current pregnancy, including results
of fetal ultrasound examinations and amniocentesis. One woman had terminated
a previous pregnancy in which the fetus was diagnosed as having severe spina
bifida and hydrocephalus, but in all other cases family history was negative
for neural tube defects. A psychosocial evaluation was performed, and fetal
imaging with ultrasonography and ultrafast MRI assessed leg movement, spinal
level of the dysraphic defect, presence of hindbrain herniation, ventricular
size, and presence of any associated anomalies. A counseling session with
members of the fetal treatment team was then held, and options were discussed.
The options available to the woman carrying a fetus with myelomeningocele
include (1) termination of the pregnancy prior to 24 weeks' gestation, (2)
serial prenatal assessment with planned cesarean delivery near term and immediate
postnatal myelomeningocele closure, or (3) fetal surgery.
Between November 1997 and March 1999, 36 women completed the evaluation.
Of these, 10 were offered and agreed to fetal surgery, based on predetermined
selection criteria. The surgeries were performed between March 1998 and February
1999. The outcome of 1 surgical procedure has been previously reported.9 The eligibility criteria for fetal closure were estimated
gestational age of 22 to 25 weeks at the time of the proposed procedure, atrial
diameter less than 17 mm, ultrasound evidence of normal leg and foot motion
without clubfoot or other leg deformity regardless of the level of dysraphism,
normal karyotype, and no other associated anomalies apart from those typically
associated with the myelomeningocele complex. Additional eligibility criteria
were no maternal medical risk factors such as obesity, diabetes, or a significant
smoking history that could complicate the perinatal course and sufficient
family support available to sustain a protracted stay in the Philadelphia
area at the Ronald McDonald House.
After obtaining signed consent from the woman, a fetal MRI was performed
using a half-Fourier acquisition single-shot turbo-spin echo sequence on a
1.5-T unit (Siemens Medical Systems Inc, Iselin, NJ). The studies were performed
with the woman usually in the supine position and used a body array coil.
Sedation was not required. Contiguous slices, 3- to 4-mm each, were obtained
of the fetal brain and spine in 3 planes orthogonal to each other. The studies
were monitored throughout by a pediatric neuroradiologist to optimize anatomic
detail and typically took 30 to 40 minutes to complete.
The initial study was performed at 19 to 23 weeks of gestation. Patients
then underwent repeat studies every 3 weeks after surgery during the pregnancy
until delivery, and the newborn underwent MRI of the brain and complete spine
as soon as he or she was medically stable.
Prior to surgery, the woman and other family members participated in
a group meeting, attended by the fetal team, consisting of the fetal surgeons,
neurosurgeon, anesthesiologists, high-risk obstetrician, neonatologist, social
worker, and perioperative nursing staff. The results of the evaluation were
presented, risks and potential benefits of the proposed surgery were reviewed,
and informed consent was obtained. All fetal surgery protocols are reviewed
by the institutional Fetal Therapy Advisory Committee.
At the start of surgery, an epidural catheter was inserted, and maternal
general anesthesia provided fetal anesthesia and uterine relaxation for open
fetal surgery.13 A low transverse maternal
laparotomy and hysterotomy were performed in a location determined by intraoperative
ultrasound examination,14 and the fetal back
was exposed. The cystic membrane of the spina bifida lesion was excised from
the neural placode and surrounding skin. The first patient underwent a single-layer
skin closure with absorbable suture, and a spinal-amniotic shunt was placed.9 At birth, the spinal drain was not functional, and
follow-up of this patient demonstrated symptomatic spinal cord tethering to
the skin flap. In the remaining patients, the procedure was modified to a
2-layer closure of acellular human dermis (Alloderm; Lifecell Corporation,
Woodland, Tex) sewn to the fascial defect and followed by primary skin closure.
No shunts were placed. In each case, the closure was accomplished in less
than one-half hour. Amniotic fluid was replaced with warmed lactated Ringer
solution, and the uterine and laparotomy wounds were closed. Postoperatively,
tocolysis was maintained with magnesium sulfate intravenous infusion and indomethacin
rectal suppositories, followed by terbutaline given by a subcutaneous pump.15 Patients were initially observed in the high-risk
obstetric unit, and the pregnant women subsequently kept at bedrest near the
hospital for the remainder of gestation. The neonates were delivered by elective
cesarean delivery at approximately 36 weeks' gestation after lung maturity
was confirmed by amniocentesis, unless premature labor resulted in earlier
The primary end points were gestational age at delivery, birth weight,
leg function in the neonatal period, need for shunt placement (head circumference
and ventricular size at birth), and severity of the Chiari malformation on
each MRI. In order to objectively evaluate the posterior fossa abnormality
based on the MRI, a grade was assigned as follows: grade 0, normal; grade
1, visible fourth ventricle and cisterna magna without cerebellar displacement
below the foramen magnum, tentorium could be vertically oriented, and tectal
beaking could be present; grade 2, visible cisterna magna without displacement
of the cerebellum below the tentorium, no visible fourth ventricle; and grade
3, displacement of cerebellum below the foramen magnum and obliteration of
all posterior fossa CSF spaces. The grade was assigned by the attending neuroradiologist
(L.T.B.). It was not possible to do this in a blinded manner, since the approximate
age of the fetus and the preoperatative or postoperative status was apparent
from the MRI studies.
All patients were delivered at the Hospital of the University of Pennsylvania
and were initially cared for by the fetal surgery group and neurosurgery group
at the Children's Hospital of Philadelphia. The investigating team made the
initial decision regarding shunt placement. Indications for shunt placement
were clinical signs of increased intracranial pressure such as macrocephaly,
fullness of the anterior fontanelle, or apnea and/or bradycardia. Patients
with stable ventriculomegaly without clinical signs did not undergo shunt
placement. After discharge from hospital, the patients were referred to a
pediatric neurosurgeon and spina bifida group in their community for follow-up
There were no maternal deaths or complications in the series and no
instances of uterine rupture. Six patients were delivered by elective cesarean
delivery at 36 weeks' gestation after confirmation of fetal lung maturity
by amniocentesis. None required respiratory support. Four newborns were delivered
earlier than planned (at 25, 30, 30, and 31 weeks' gestation) because of premature
labor, and all required initial ventilatory assistance. The 25-week gestation
newborn weighed 745 g at birth and died of respiratory insufficiency at age
2 days. The other 3 premature newborns survived. All 9 surviving newborns
were discharged to their homes at a mean age of 23 days (range, 4-63 days)
and have been followed up for a mean of 182 days (range, 77-473 days).
The myelomeningocele closure was initially well healed in all cases;
however, 1 patient (patient 5) required reclosure at age 1 week because of
CSF leakage. At the repeat operation, tethering of the spinal cord to the
lateral dural wall, but not to the Alloderm graft, was observed. Another patient
(patient 1) required a tethered cord release from the overlying skin (Alloderm
was not used) at age 7 months because of loss of leg function below the hips,
which was not regained after the procedure. One patient (patient 4) required
ventriculoperitioneal shunt placement at age 2 weeks because of frequent apnea
episodes in association with mild ventriculomegaly. The anterior fontanelle
of this patient was soft, and there were no other signs or symptoms of intracranial
hypertension, but the apnea episodes promptly resolved after the procedure.
Two patients were offered shunt placement by the treating neurosurgeon in
the families' community based on stable ventriculomegaly without clinical
signs of intracranial hypertension or developmental delay, but, after further
consideration, shunt placement has not yet been performed in these patients.
The hindbrain abnormality was scored as grade 3 in all of the early
fetal (19-24 gestational weeks) preoperative MRIs and reflected hindbrain
herniation below the foramen magnum and absence of CSF spaces around the brainstem
(Figure 1). On the MRI scan done at 3 weeks after fetal closure, all 9 of the surviving
fetuses showed improvement; 4 now were rated as grade 2 and 5, as grade 1.
By the 6-week MRI, all of the patients were grade 1 (Table 1). The MRI scans performed shortly after birth were also
grade 1 (Figure 1). None of these
scans showed tonsillar or vermian displacement below the foramen magnum, and
all had visible CSF spaces corresponding to the fourth ventricle and cisterna
magna, although a vertical tentorium and beaking of the tectum were apparent
in all of the patients. At 1 to 13 months of follow-up, none of the infants
have manifested clinical signs or symptoms referable to the Chiari II malformation.
Five of 9 evaluable patients had newborn lower extremity function better
than expected by at least 2 spinal levels based on anatomic level as determined
from the initial fetal MRI. Three patients with thoracic or high lumbar level
lesions had function at the L5 level or better (Table 1). Bowel and bladder continence cannot be evaluated yet because
of the young age of the infants.
While fetal surgery has become an accepted treatment for some fatal
conditions,14,15 the appropriateness
of fetal surgery for nonlethal conditions is controversial.16
Early experiences with fetal ventriculoamniotic shunt placement for severe
hydrocephalus were disappointing, and a moratorium was eventually invoked.
Recent advances in open fetal surgical techniques and tocolysis have prompted
a reexamination of the role of fetal surgery in improving quality of life
in certain nonlethal conditions. Although extensive efforts to prevent and
detect neural tube defects have resulted in a marked reduction in the number
of affected infants, myelomeningocele remains a devastating problem for which
postnatal therapy is palliative at best.17
Problems include lower extremity paralysis, shunt-dependent hydrocephalus,
bowel and bladder incontinence, and brainstem dysfunction from the Chiari
Studies in experimental animals suggest that exposure of fetal neural
tissue to the intrauterine environment results in secondary damage to the
exposed spinal cord in addition to any dysfunction attributable to the primary
spinal cord abnormality.18,19
These experiments involved a surgically created defect, which was not entirely
analogous to human myelomeningocele. The models did not produce any of the
associated anomalies seen in human myelodysplasia, such as hydrocephalus or
the Chiari II malformation. Furthermore, these animal experiments did not
resolve the question of when human nervous tissue might be vulnerable during
A limited amount of human data also provides evidence that at least
some of the components of the spina bifida complex are acquired in utero.
Autopsy material obtained from human embryos and fetuses with myelomeningocele
suggests that neural degeneration occurs at some point during gestation.20,21 In 18 embryos with classic caudal
myelodysplasia, Osaka et al7 found an everted
neural plate, but most of the membrane coverings were preserved. Interestingly,
there was no Chiari II malformation seen in these embryos, whereas the malformation
was present in the 2 fetuses with caudal myeloschisis from the same series.
Similarly, hydrocephalus was not present in the embryos, but was found in
1 fetus. Babcook et al8 performed serial sonograms
on human fetuses with myelomeningocele and found that, whereas only 44% of
fetuses aged 24 gestational weeks or younger had ventriculomegaly, 94% of
fetuses older than 24 gestational weeks had ventriculomegaly. Furthermore,
the degree of hydrocephalus correlated with the amount of posterior fossa
Early experience with fetal myelomeningocele closure in humans suggested
a lower than expected incidence of hindbrain deformity in these infants once
they were born. The Chiari II malformation with displacement of cerebellar
tissue below the foramen magnum is seen in virtually all newborns with myelodysplasia,22- 25 but
cerebellar herniation was not present in our first case after early gestation
fetal closure9 nor in the 4 cases of late gestation
fetal closure reported by Tulipan et al.12
Our previously reported case (patient 1 in the present report) has not required
shunt placement at 1 year of follow-up; however, 2 of 4 patients in the series
described by Tulipan et al required shunt placement, perhaps because of the
late gestation closure.
The major finding in the current series is the rapid reversal of hindbrain
herniation and overall increase in the posterior fossa CSF spaces as documented
by serial fetal MRI in all 9 surviving fetuses who underwent open myelomeningocele
closure at 22 to 25 weeks of gestation. Definite improvement of the Chiari
II malformation was evident in all patients on an MRI obtained 3 weeks after
the closure. None of the 9 patients had cerebellar herniation present on the
newborn MRI, and all patients had a visible fourth ventricle and cisterna
magna, which suggests patency of the CSF pathways. Beaking of the midbrain
and a vertically oriented tentorium were present in all surviving patients,
and so a designation of normal was precluded. However, at present there is
no reason to ascribe any adverse consequences to these residual abnormalities.
Follow-up in this series of patients has been short, but only 1 of our 9 patients
has required shunt placement for clinically overt hydrocephalus, although
most of the patients have some degree of ventricular enlargement.
It would be desirable to compare our series with a control cohort of
patients who did not undergo fetal closure to eliminate selection bias. Our
strict selection criteria for fetal closure arguably preselect a favorable
group of patients who might not have required shunt placement even if they
had not undergone fetal closure. It is unlikely that a suitable control group
can be assembled. Patients who were not considered candidates for fetal closure
at our institution would not have been comparable, and the mothers of such
patients often either went elsewhere to undergo the fetal procedure or elected
to terminate the pregnancy. Women who were offered the procedure invariably
chose to proceed with it. Nonetheless, reversal of preexisting hindbrain herniation
on serial scans coupled with the almost universal presence of the Chiari malformation
in the untreated newborn seen historically is compelling.
Reversal of hindbrain herniation after early fetal closure lends support
to the unified mechanism of embryogenesis proposed by McLone and Naidich,2 who suggest that the myelomeningocele allows excessive
drainage of ventricular CSF through the open defect and leads to collapse
of the rhombencephalic vesicle and a small posterior fossa volume. Growth
of the cerebellum and brainstem within a small posterior fossa results in
downward herniation and caudal displacement of the cerebellar vermis and brainstem
into the cervical spinal canal. Because the outlet of the fourth ventricle
is occluded by impacted brain tissue, obstructive hydrocephalus develops either
in the fetal period or in the newborn period after closure of the myelomeningocele
eliminates the spinal defect as a drainage pathway. By closing the spinal
defect early in fetal life, it is likely that back pressure is again established
in the posterior fossa, which disimpacts the brain from the spinal canal and
reestablishes a more normal CSF drainage pathway (Figure 2). Ventricular enlargement, once established, does not appear
to resolve, which may be because of the high compliance of the fetal brain.
The absence of overt signs of increased intracranial pressure or significant
progression of ventriculomegaly seen in these patients suggests a "compensated,"
probably communicating, type of hydrocephalus.
Whether longer follow-up will demonstrate a delayed requirement for
shunt placement in these patients is unknown. Preventing the problems associated
with lifelong shunt dependency as well as those problems associated with brainstem
dysfunction attributable to the Chiari malformation itself probably justifies
the procedure if the risk can be kept to a minimum and if long-term follow-up
confirms that the benefit is maintained. The major risk in all fetal operations
is premature labor. The rationale for performing the operation later in fetal
life is that if premature labor cannot be controlled, the newborn would have
fewer of the well-known complications associated with low birth weight. We
have chosen to perform the closure earlier in fetal life, on the grounds that
the potential for reversal of secondary injury is more likely to occur. This
approach may permit preservation of the regenerative potential of the unmyelinated
spinal cord,26 obviate third trimester damage
to the spinal cord, and allow intervention early in the course of progressive
ventriculomegaly typical of myelomeningocele fetuses. There was 1 death in
our series, directly attributable to lung immaturity in a 745-g newborn, and
3 other patients were delivered prematurely at about 30 weeks' gestation.
None of the surviving patients have suffered intraventricular hemorrhage,
major retinopathy, bronchopulmonary dysplasia, or other apparent long-term
consequences of prematurity. Risk to the mother appears minimal, since there
were no maternal complications.
Five of our surviving patients appeared to have better leg function
by at least 2 spinal segments than would have been expected based on fetal
imaging studies, although in the first case this was lost by 7 months because
of spinal cord tethering to the skin flaps. Although there is very good correlation
of prenatally determined anatomic level with ultimate motor outcome in children
with spina bifida,23,27 short
follow-up time, lack of a control group, and a relatively small number of
patients prevent drawing any firm conclusions regarding leg function in these
infants. However, the data are sufficiently promising to warrant offering
fetal closure to selected patients.