Fetal surgery for spina bifida: Past, present, future

Abstract

Open spina bifida or myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. Experimental and clinical evidence suggest that the primary cause of the neurologic defects associated with MMC is not simply incomplete neurulation, but rather chronic, mechanical and amniotic-fluid induced chemical trauma that progressively damages the exposed neural tissue during gestation. The cerebrospinal fluid leak through the MMC leads to hindbrain herniation and hydrocephalus. In utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. In the past, studies in animal models and clinical case series laid the groundwork for a clinical trial to test the safety and efficacy of fetal MMC repair. In the present, a prospective, randomized study (the MOMS trial) has shown that fetal surgery for MMC before 26 weeks' gestation may preserve neurologic function, reverse the hindbrain herniation of the Chiari II malformation, and obviate the need for postnatal placement of a ventriculoperitoneal shunt. However, this study also demonstrates that fetal surgery is associated with significant risks related to the uterine scar and premature birth. In the future, research will expand our understanding of the pathophysiology of MMC, evaluate the long-term impact of in-utero intervention, and to refine timing and technique of fetal MMC surgery using tissue engineering technology.

Introduction

Open spina bifida or myelomeningocele (MMC) is a devastating congenital defect of the central nervous system for which there is no cure. The natural history of MMC includes a constellation of findings which correlate with the proximal anatomic extent of the defect. MMC is characterized by protrusion of the meninges and spinal cord through open vertebral arches leading to lifelong paralysis. In addition, MMC patients are often limited by various degrees of mental retardation, bowel and bladder dysfunction, and orthopedic disabilities. While the etiology of MMC remains poorly understood, primary failure of either neural tube or mesenchymal closure at the caudal neuropore in the embryonic period results in exposure of the developing spinal cord to the uterine environment.1, 2 Without protective tissue coverage, secondary destruction of the exposed neural tissue by trauma or amniotic fluid may occur throughout gestation. Until 15 years ago, treatment of MMC consisted of surgical closure of the spinal canal at birth and lifelong supportive care. Since that time the clinical experience with midgestational human repair has been shown to improve neurologic function and reduce morbidity from hydrocephalus and the Arnold–Chiari II malformation by reversal of the hindbrain herniation component. This review will focus on the rationale for in utero repair in the context of pathologic observations and animal models of MMC, outcomes from human fetal MMC repair including the recently completed Management of Myelomeningocele Study (MOMS trial), and future research challenges.

Advances in prenatal diagnosis now permit diagnosis of spina bifida as early as the first trimester, and extensive research into the etiology of neural tube defects has elucidated both genetic and micronutrient causes.³ While substantial progress could be made in preventing this disorder through folic acid supplementation, the impact of this preventative approach has leveled off.4, 5 Consequently, spina bifida affects 1 in 3000 live births.6, 7, 8 Not included in this figure are the estimated 25–40% of MMC pregnancies in which the fetus is aborted.9, 10 Mothers who choose to continue the pregnancy must prepare for a child with significant care needs and high medical expenses. Despite aggressive intervention, nearly 14% of all spina bifida neonates do not survive past 5 years of age, with the mortality rising to 35% in those with symptoms of brainstem dysfunction secondary to the Arnold–Chiari malformation.¹¹ While 70% of patients have an I.Q. above 80, only half are able to live independently as adults, even with adapted accommodations.¹² The emotional and financial impact on the family and community are enormous. No recent data are available, but in 1994 the cost of care exceeded $500 million per year (in 1992 dollars) in the United States alone.¹³

In addition to motor and sensory deficits due to the spinal cord lesion, significant complications in MMC come from hydrocephalus, the Arnold–Chiari II malformation, and spinal cord tethering at the site of surgical repair. Hydrocephalus, defined as any enlargement of the cerebral ventricles, occurs in more than 85% of patients with MMC.¹⁴ More than 80% of spina bifida patients require placement of shunts to prevent the neurologic and intellectual compromise that accompanies significant ventriculomegaly, and 46% have complications of shunts within the first year of placement.15, 16 Almost all patients with MMC also have the Arnold–Chiari II malformation, characterized by descent of the cerebellar vermis through the foramen magnum, elongation and kinking of the medulla, caudal displacement of the cervical spinal cord and medulla, and obliteration of the cisterna magna.¹⁷ Descent of the hindbrain through the foramen magnum can lead to brain stem compression, the leading cause of mortality in children with MMC.¹⁸ Clinical presentation of this malformation depends on the age of the child, but typically it includes dysfunction of the cerebellum, medullary respiratory center, and cranial nerves IX and X as well as hydrocephalus. Surgical management for symptomatic hindbrain herniation is beneficial in only selected patients and consists of a ventricular shunt, though some patients ultimately require laminectomy and decompression of the cranio–cervical junction.19, 20 Tethering is fixation of the spinal cord secondary to adhesions between the previously exposed neural elements and the surrounding tissues, leading to tension on the neural axis. The diagnosis is confirmed radiographically, usually after a patient develops progressive worsening of neurologic function. While surgical release can limit further damage in some patients, the functional decline may be irreversible in others.21, 22 Therapeutic interventions aimed at preventing these complications could significantly impact the quality of life of children with MMC. In utero intervention may hold the key for reversing the hindbrain herniation, limiting the need for ventriculoperitoneal shunting due to hydrocephalus, and preventing late loss of function due to tethering.