Myelomeningocele (MMC) is a costly lifetime disease with many comorbidities, including sensory and motor lower limb disability, bladder/bowel dysfunction, scoliosis, club foot, and hydrocephalus. MMC treatment options have changed over time because routine use of fetal ultrasonography and MRI has provided prenatal diagnosis and the potential for fetal surgery. There is still no consensus on how to treat the MMC diagnoses prenatally, mainly related to the infrastructure required to operate on pregnant patients. This article provides an overview of prenatal and postnatal MMC repair and the features in the prenatal diagnosis.
Key points
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Myelomeningocele is a chronic disease that leads to significant disabilities, including sensory disturbances and weakness of the lower extremities.
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Prenatal ultrasonography and MRI have enabled earlier diagnosis of these patients.
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Prenatal myelomeningocele correction has shown good outcomes by reducing the ventriculoperitoneal shunt rate, and by improving ambulation status and mental development.
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Postnatal treatment of myelomeningocele continues to be the standard of care in many institutions.
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Antenatal myelomeningocele repair requires a multidisciplinary program not available in many institutions and should be discussed as a treatment option with new patients.
Introduction
Myelomeningocele (MMC) is a chronic disease that affects 0.3 to 0.72 per 1000 live-born and stillborn babies in the United States. MMC has a lifetime cost estimated at more than $620,000 in 2011 for each child born with MMC, which comprises direct medical costs, special education, caregiver needs, and loss of employment potential.
MMC is an open neural tube defect that is fairly simple to correct, but consequences remain with patients for a lifetime. Patients with MMC often have morbidities related to lower limb sensory/motor impairment, ranging from weakness/hypoesthesia to paraplegia/anesthesia, bowel/bladder dysfunction, spinal and lower limb deformities (scoliosis, hip/ankle deformities, and club foot), and hydrocephalus. Hydrocephalus affects as many as 85% of the patients with MMC operated after birth and also requires a lifetime of management.
New imaging modalities (fetal ultrasonography and MRI) have facilitated prenatal diagnosis of MMC and have made possible prenatal MMC treatment, a key driver for the development of fetal surgery. Prenatal treatments were recently compared with the standard of care in a clinical trial. However, this new treatment paradigm has generated several controversies, mainly regarding the maternal morbidity and premature birth of the fetus. This article reviews postnatal MMC repair, the features in the prenatal diagnosis, and prenatal MMC repair, and discusses the results and controversies concerning prenatal and postnatal MMC treatment.
Introduction
Myelomeningocele (MMC) is a chronic disease that affects 0.3 to 0.72 per 1000 live-born and stillborn babies in the United States. MMC has a lifetime cost estimated at more than $620,000 in 2011 for each child born with MMC, which comprises direct medical costs, special education, caregiver needs, and loss of employment potential.
MMC is an open neural tube defect that is fairly simple to correct, but consequences remain with patients for a lifetime. Patients with MMC often have morbidities related to lower limb sensory/motor impairment, ranging from weakness/hypoesthesia to paraplegia/anesthesia, bowel/bladder dysfunction, spinal and lower limb deformities (scoliosis, hip/ankle deformities, and club foot), and hydrocephalus. Hydrocephalus affects as many as 85% of the patients with MMC operated after birth and also requires a lifetime of management.
New imaging modalities (fetal ultrasonography and MRI) have facilitated prenatal diagnosis of MMC and have made possible prenatal MMC treatment, a key driver for the development of fetal surgery. Prenatal treatments were recently compared with the standard of care in a clinical trial. However, this new treatment paradigm has generated several controversies, mainly regarding the maternal morbidity and premature birth of the fetus. This article reviews postnatal MMC repair, the features in the prenatal diagnosis, and prenatal MMC repair, and discusses the results and controversies concerning prenatal and postnatal MMC treatment.
Postnatal repair of myelomeningocele
Despite the new emphasis on the antenatal correction of MMC recently published in the Management of Myelomeningocele Study (MOMS) trial, postnatal repair of MMC continuous to be a standard of care in many institutions in the United States and around the world. It is important to highlight that, even as a standard of care, the postnatal repair of MMC has many difference among centers caring for the patients with MMC. A German study that enrolled 57 neurosurgery departments and 18 pediatric surgery departments surveyed the centers about management of open MMC in their hospitals. Significant differences in the therapeutic decisions were reported, including the type of delivery, timing to treat the MMC after birth, type of preoperative diagnostic image tool, type of prophylactic antibiotics, timing to treat hydrocephalus, and type of valve used to treat hydrocephalus.
Guidelines regarding management of MMC currently do not exist. With the completion of the MOMS trial, prenatal repair should now be discussed with each newly diagnosed patient as a potential option for treatment. For those patients who will be repaired after birth, the first issue after the antenatal diagnosis of an MMC is the type of delivery. Many centers prefer the cesarean section as a route of delivery, advocating that this route is safer and protective to the neonate, the meningocele sac, and to the neural tissue/placode. However, there is no consensus to date because of the absence of a randomized clinical trial studying this question. One cohort study, conducted by Luthy and colleagues, showed better motor functions at the age of 2 years for those patients delivered by cesarean section before labor compared with those delivered by vaginal route or cesarean section after labor. In contrast, other cohort studies designed to investigate the motor function after birth did not find any outcome difference between vaginal and cesarean section delivery. Despite the possible controversy, elective cesarean section remains attractive to many centers because it allows the scheduling of the MMC correction after birth and transforms a possible urgent surgery in an elective correction that benefits the newborn.
The timing of MMC repair has changed over the past 50 years. Before the 1960s, mortality and infection rates in patients with MMC were as high as 90% and in this scenario many neurosurgeons opted for conservative treatment with MMC defects left to heal by reepithelialization. With introduction of the Holter valve to treat hydrocephalus, the mortality of patients with MMC decreased significantly. The neurologic impairment, which was until then considered a secondary issue, became more evident.
By the 1960s some researchers, concerned with the poor neurologic outcomes of patients with MMC, started to compare conservative versus operative repair of MMC. The first randomized clinical trial conducted by John and colleagues enrolled 20 patients for each operative and nonoperative group, and the study had to be stopped because of improved outcomes for patients operated on within 48 hours. They had improved outcomes related to mortality, fewer wound infection, hydrocephalus, meningitis and ventriculitis, and muscle strength, and an improved hospital length of stay. Thus the investigators concluded that the MMC should be repaired as a surgical emergency.
Since then, many cohort and case series studies have reported an increase in the infection rates for those patients operated after 48 hours of life, a decrease in the wound dehiscence and neurodevelopment delay at age 1 year for those patients operated immediately after birth, and also an increase in infection rates and length of hospitalization for those patients operated after 24 hours of birth. Thus the data suggest that the early repair of MMC is a goal to be achieved in order to improve patients’ outcomes. Most of the cohort studies and the only randomized trial showed better results when the MMC was repaired within 48 hours of birth. However, even the most aggressive treatment after birth has not shown a reduction in the hydrocephalus rate.
Hydrocephalus in patients with MMC repaired after birth occurs at an approximate frequency of 82% at 12 months after birth. The pathophysiology of hydrocephalus in the context of MMC and Chiari II malformation is complex and has not been well established. McLone and Knepper proposed a theory that neurulation failure in the MMC leads to an open defect in the distal neural tube, creating a cerebrospinal fluid leakage that consequently causes a lack of distention of the rhombencephalic vesicles. This lack of distention in turn alters the inductive effect in the mesenchymal and endochondral bone formation of the posterior fossa, generating a small posterior fossa, a downward tonsils herniation, and a brainstem displacement, and thus the hydrocephalus in this context is related to the malformation of the cerebrospinal fluid pathways in the small posterior fossa.
Given the high rates of hydrocephalus related to MMC in patients undergoing postnatal correction, some studies were designed to assess the advantages associated with performing the MMC correction and implantation of the ventriculoperitoneal shunt in the same time. Although those studies have shown safety, low infection rates, and improved wound healing in patients with MMC, limitations of this approach are that no study has identified a rate of hydrocephalus even close to 100%. Furthermore, patients undergoing ventriculoperitoneal shunt surgery are subject to a dysfunction rate that can be as high as 45.9% in the first year. Despite being safe, the performance of 2 simultaneous operations is not a common practice because of a decreasing incidence of shunt placement in the MMC population. Therefore, there is not a preestablished best time to perform placement of a ventriculoperitoneal shunt. To standardize indications for ventriculoperitoneal shunt placement in the MOMS trial, specific criteria were defined and are listed here.
At least 2 of the following are required for shunt placement:
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An increase in the greatest occipital-frontal circumference adjusted for the gestational age defined as crossing percentiles. Patients who cross centiles and subsequently plateau do not meet this criterion.
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A bulging fontanel (defined as above the bone assessed when the baby is in an upright position and not crying) or split sutures or sunsetting sign (eyes appear to look downward with the sclera prominent over the iris).
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Increasing ventricular measurements on consecutive imaging studies determined by increase in ratio of biventricular diameter to biparietal diameter according to the method of O’Hayon and colleagues.
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Head circumference greater than the 95th percentile for gestational age.
At least 1 of the following criteria is required for shunt placement:
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Presence of marked syringomyelia (syrinx with expansion of spinal cord) with ventriculomegaly (undefined).
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Ventriculomegaly (undefined) and symptoms of Chiari malformation (stridor, swallowing difficulties, apnea, bradycardia).
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Persistent cerebrospinal fluid leakage from the MMC wound or bulging at the repair site.
Tulipan and colleagues analyzed the prerandomization risks of patients in the MOMS trial and found that 25% of patients in the postnatal group presented with persistence of cerebrospinal fluid leakage or bulging of the wound as the criterion for placement of ventriculoperitoneal shunt compared with 1.1% of the intrauterine operated group, and this criterion accounted for 60% of the difference in the placing ventriculoperitoneal shunts between the two groups. In a different study, Chakraborty and colleagues reported rates of ventriculoperitoneal shunt placement at 51.9% in patients operated for MMC after birth when they standardized criteria for shunt placement. They tolerated moderate and increasing ventricular dilatation, and treated the operative fistula wound as a local complication and not as a criterion for hydrocephalus. However, other investigators have reported that cerebrospinal fluid leakage in the MMC wound was a risk factor for meningitis or ventriculites.
Prenatal diagnosis of myelomeningocele
The routine use of two-dimensional prenatal ultrasonography has facilitated the prenatal diagnosis of MMC and rachischisis with increasing frequency. Accurate diagnosis of the disease and identification of the level of the lesion are now possible for counseling purposes. Ultrasonography is 90% sensitive and is often complimented by fetal MRI. Evaluation of the fetal spine by ultrasonography and cranial signs of spinal dysraphism can be evaluated from the 12th week of gestation. For the evaluation of the fetal spine, a full sweep in sagittal, coronal, and transverse sections of the spine is recommended, with a focus on vertebral bodies in the spinal canal and medulla.
Two-dimensional prenatal ultrasonography in association with three-dimensional ultrasonography allows a detailed analysis of the spinal characteristics of MMC, such as the type of spinal dysraphism (meningocele, MMC, or rachischisis; Fig. 1 ), the anatomic level of the lesion ( Fig. 2 ), alterations of the curvature of the spine, associated malformations of the spinal (syringomyelia and diastematomyelia), and the degree of herniation in the posterior fossa structures near the foramen magnum ( Fig. 3 ).
Cranial ultrasonography can be used to identify cranial features of MMC that include the following: the lemon sign, which represents the so-called dry brain and features fetal intracranial hypotension ( Fig. 4 ) ; ventriculomegaly assessed at the level of the atrium in the lateral ventricle (abnormal when >10 mm), which is present in 70% to 90% of fetuses with an MMC (the characteristic pattern is colpocephaly); and the banana sign, which describes the echography findings in the axial plane of the cerebellar herniation through the foramen magnum ( Fig. 5 ). These 3 cranial signals have a specificity of 99% in MMC, but they may also be present in normal fetuses of obese mothers.
Ultrasonography can also be used to infer the degree of impairment of the lower limbs in fetuses with MMC by identifying the presence of clubfoot and the degree of tropism of the lower limbs. It is possible to deduce the amount of fat that is replacing the skeletal muscle in the presence of severe paralysis of the lower limbs. When actively evaluated, the movement of the lower limbs can show a good prognosis compared with the presence of bilateral clubfeet. Notably, open dysraphism can produce involuntary movements of the fetus, leading to a false diagnosis.
Prenatal Imaging Assessment: Fetal MRI
Fetal MRI is a complimentary diagnostic imaging modality to ultrasonography. MRI is performed with ultrafast sequences to minimize the adverse effects of signs of maternal and fetal movements. T2-weighted (T2-W) images are enough for most of the information used for the diagnosis, including single-shot fast spin-echo or half-Fourier acquisition single-shot turbo spin-echo sequences at minimal slice thickness (2–4 mm). Gadolinium is not used as a contrast agent because is retained for a long period in the fetus–amniotic fluid system, and is not necessary for the diagnosis of MMC. The excellent soft tissue contrast resolution between the cord and the surrounding cerebrospinal fluid allows improved delineation of abnormal structures ( Fig. 6 ). This delineation is important for the detection of other closed spinal dysraphisms, such as lipomyelomeningocele, and other central nervous system malformations such as the callosal dysgenesis/hypogenesis, periventricular nodular heterotopy, cerebellar dysplasia, syringohydromyelia, and diastematomyelia.
Prenatal repair of myelomeningocele
Fetal surgery requires the work of a multidisciplinary team (obstetrician, neurosurgeon, neonatologist, geneticist, anesthesiologist, nurse, physiotherapist, psychologist, and orthopedists, among others) in which each professional has a role and is interacting at all times of the treatment. Increased maternal risks are inherent to the procedure and the use of anesthetics, tocolytics, and other medications. Fetal surgeons should have the ability to correct anomalies in fetuses that are less than 27 weeks together with the capacity to maintain stable maternal and fetal hemodynamic conditions throughout the procedure. Prenatal repair of patients with MMC should occur between gestational age 19 and 27 weeks and 6 days, at a maternal age of at least 18 years, for Chiari type II spinal dysraphism ranging between T1 and S1, and for normal fetal karyotypes, with the cases that did not meet these criteria to be evaluated and discussed in a multidisciplinary forum before proceeding to surgery.
The initial experience of the Brazilian group shows that the results of the MOMs trial can be applied to create a highly successful program even outside the United States. Obstetricians perform a 5-cm hysterotomy. After the hysterotomy, the fetus is positioned so that the neurosurgeon can perform correction of the MMC. The most important step is the release of the cord and the treatment of the tethered spinal cord. Often a fibrotic band is found while fixing the top part of the placode to the dura mater, which is called the cava ligament. This ligament is found in more than 90% of cases of MMC. Some investigators recommend using artificial grafts to close the dura mater. This procedure is intended only to protect the neural tissue from the amniotic fluid and intrauterine trauma. After reconstruction of the placode to its original form, the dura and fascia are closed in a watertight fashion. In addition, the skin is closed with an absorbable continuous suture. After closure of the MMC, the fetus is released into the uterine cavity. The amniotic fluid is replaced and the uterus is closed.
Fetal neurosurgery entails the monitoring of the fetus from the moment of birth to the postnatal period. It is clear that the more delayed the delivery, the better the conditions of the newborn, but maternal health should be taken into consideration, particularly the quantity of the amniotic fluid and the thickness of the surgical scar. The rupture of amniotic membranes and the transition to oligohydramnios indicate the anticipation of labor, as well as the thinning of the uterine scar. If a thinning of the uterine scar is detected, early childbirth can prevent uterine rupture. Postoperative fetal monitoring includes observation of the MMC scar, calculation of ventricular size, and determination of the degree of both brainstem and tonsillar herniation.
Outcomes of Postnatal Versus Prenatal Myelomeningocele Correction
Recently the outcomes of postnatal and prenatal MMC correction were evaluated in the MOMS trial, which was terminated because of benefits in the prenatal group. The objective of the MOMS trial was to assess the results of intrauterine surgery compared with postnatal surgery. The primary end point of the MOMS trial was to analyze the fetal or neonatal mortality and the incidence of ventriculoperitoneal shunts until 1 year of age. The secondary end point was an evaluation of cognitive and motor development at 30 months of age. The main inclusion criteria were pregnancy, MMC from level T1 to S1, a gestational age between 19 and 25 weeks 6 days, a randomized and normal karyotype, and a maternal age of more than 18 years. The major exclusion criteria were fetal anomalies unrelated to MMC, severe kyphosis, risk of premature birth (including short cervix and previous preterm delivery), and placental abruption. The study showed a statistically significant reduction in incidence of hydrocephalus and need for ventriculoperitoneal shunts compared with the prenatal group (40% vs 82%). In addition, Tulipan and colleagues in a recent update of the MOMS cohort reported that the main prenatal risk factor for the shunt placement was the ventricle size; fetuses with ventricle size less than 10 mm had 20% of shunt placement, those with ventricle size between 10 mm and up to 15 mm had 45.2%, and those with ventricles larger than 15 mm had 79% of shunt placement. Moreover, 42% of the prenatal group presented with an independent gait at 30 months of life compared with 21% in the postnatal group ( P <.001). Chiari malformation II was reversed in 36% of the prenatal group compared with only 4% of the postnatal group; the symptomatic Chiari II index was 6% and 22%, respectively. Larger studies are required for a better understanding of the evolution of vesical and intestinal sphincteric function, in addition to sexual function in these patients. Fetal benefits should be evaluated from the perspective of increased maternal risk caused by the increased incidence of complications such as premature rupture of membranes (46%), premature birth (79%), and the observed mean gestational age at birth of 34.1 weeks in the fetal surgery group compared with 37.3 weeks in the postnatal surgery group. In addition, a uterine scar from a hysterotomy resulted in various complications, including varying degrees of weakness of the uterine wall in 25% of the women at birth, 9% partial rupture, and 1% total rupture of the uterine scar.
Although the MOMS trial used strict inclusion and exclusion criteria for its study patients, in everyday practice, clinicians tend to be less rigid. Patients with controlled hypertension, diabetes, and some types of autoimmune diseases, such as systemic lupus erythematosus, can undergo the procedures.
Surgery is not recommended in cases with kyphoscoliosis and injury above L1. Ventriculomegaly greater than 16 mm is a formal MOMS exclusion criterion. In the Brazilian case series (update of initial publication), ventriculomegaly greater than 20 mm is a contraindication for prenatal repair of MMC. Many patients have colpocephaly but are not truly hydrocephalic. Five patients in our series had ventriculomegaly greater than 16 mm, and in 1 case there was a need for a ventricular shunt after birth. Age and weight are other important factors as well. For some patients with a body mass index greater than 35, the authors have also recommended surgery. In a series of 200 patients who underwent surgery for correction of MMC in utero in Santa Joana Hospital and Maternity Center of São Paulo, Brazil, and the Federal University of São Paulo (UNIFESP), Paulista Medical School (update of initial publication), gestational age at operation ranged from 24 to 27 2/7 weeks ( Table 1 ). Eighteen cases (9%) were born at less than 30 weeks of gestation, 74 (37%) cases were born between 30 and 34 weeks, 70 (35%) cases were born between 35 and 36 weeks, and 38 (19%) cases were born after 37 weeks. On average, the gestational age at birth was 34 weeks. Perinatal mortality occurred in 4 cases (2%), 2 of which were caused by chorioamnionitis, 1 was caused by a premature rupture of membranes, and another was caused by idiopathic bradycardia.
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