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Myelomeningocele
Marvin A Fishman, MD
Grace B Villarreal, MD
UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on May 16, 2006. The next version of UpToDate (14.3) will be released in October 2006.
INTRODUCTION — Neural tube defects (NTDs) are the second only to cardiac malformations as the most prevalent congenital anomaly in the United States. Of these, myelomeningocele, anencephaly, and encephalocele are most common abnormalities. The clinical features, diagnosis, and management of myelomeningocele are reviewed here. Prenatal aspects and anencephaly and encephalocele and prevention of neural tube defects are discussed separately. (See "Prenatal screening and diagnosis of neural tube defects", see "Ultrasound diagnosis of neural tube defects" see "Anencephaly and encephalocele" and see "Prevention of neural tube defects").
EMBRYOLOGY OF NEURAL TUBE — The central nervous system (CNS) appears as a plate of thickened ectoderm called the neural plate at the beginning of the third week of embryonic life. The lateral edges of the neural plate become elevated to form the neural folds. These folds subsequently become further elevated, approach each other, and fuse to form the neural tube; the fusion begins in the cervical region and proceeds in both the cephalad and caudal directions. However, fusion is delayed at the cranial and caudal ends of the embryo so that the cranial and caudal neuropores form open communication between the lumen of the neural tube and the amniotic cavity. Closure of the cranial neuropore occurs on the 25th day after conception and closure of the caudal neuropore occurs approximately two days later [1]. Neural tube defects result from failure of the neural tube to close normally between 25 and 28 days after conception.
Myelomeningocele — Myelomeningocele (also known as myelocele and meningomyelocele), is due to failure of closure of the posterior neural tube. This leads to malformation of the vertebral column and spinal cord and other CNS anomalies. In severe forms, the neural plate appears as a raw, red, fleshy plaque through a defect in the vertebral column (known as spina bifida) and the integument. A protruding membranous sac containing meninges, CSF, nerve roots, and dysplastic spinal cord often protrudes through the defect. The majority of patients with myelomeningocele also have hydrocephalus and Chiari II malformations [2].
If disturbances occur during earlier stages of neural tube formation, canalization, and retrogressive differentiation, the resulting lesions are covered by skin. Approximately 10 percent of patients with spina bifida have a meningocele, in which only the meninges of the spinal cord herniate through the vertebral defect.
ETIOLOGY — The cause of NTDs is unknown. The majority are isolated malformations of multifactorial origin. NTDs also occur as part of syndromes, in association with chromosomal disorders, or as a result of an environmental exposure (show table 1) [3-9]. (See "Prenatal screening and diagnosis of neural tube defects").
Genetic factors — A genetic factor is suggested by the observations that NTDs have a high concordance rate in monozygotic twins, are more frequent among siblings, and are more common in females compared to males [10]. In addition, there is a high prevalence of karyotypic abnormalities among fetuses with NTDs, especially in the presence of other congenital anomalies. For example, a large study evaluating the frequency of aneuploidy in pregnancies with fetal NTDs found aneuploidy in 7 percent of affected cases [11]. The majority of the abnormal karyotypes were trisomies and most of the trisomic fetuses also had multiple congenital anomalies. A second series reported a similar rate (6.5 percent) of chromosomal abnormalities in fetuses with NTDs [12]. These data support the use of fetal karyotyping as an aid in diagnostic evaluation and recurrence risk counseling [11,12].
Folic acid deficiency — Adequate folate is critical for cell division due to its essential role in the synthesis of nucleic and certain amino acids. Folic acid deficiency has been implicated in the development of NTDs (folate sensitive NTDs) and folate supplementation has been shown to reduce the risk of NTDs. (See "Prevention of neural tube defects", section on Relationship between folate and NTDS).
Folic acid antagonists — Administration of folic acid antagonists (dihydrofolate reductase inhibitors and others) increases the risk of NTDs. In a large case-control study, the risk of NTDs (spina bifida, anencephaly, and encephalocele) was greater with than without exposure to folic acid antagonists (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) in the first or second month after the last menstrual period (adjusted odds ratio 2.8, 95% CI 1.7 to 4.6) [13]. The biologic mechanism for this association is largely unknown. (See "Risks associated with epilepsy and pregnancy" section on Antiepileptic drugs).
****bolic disorders — Genetic abnormalities involving the ****bolism of folate and homocysteine may account for some cases of NTDs [14]. These disorders may explain why supplementation with folic acid reduces but does not eliminate the risk of NTD. Genes affecting folate ****bolism include those encoding methylene tetrahydrofolate reductase and methylene tetrahydrofolate dehydrogenase. Those affecting homocysteine ****bolism include those encoding methionine synthase; its regulator, methionine synthase reductase; and cystathionine synthase.
Disruptive factors — Some cases of encephalocele may be due to disruptive factors. Encephalocele has been associated with amniotic bands, maternal hyperthermia between 20 and 28 days of gestation [15], and warfarin embryopathy [16].
INCIDENCE — The incidence of NTDs (of which myelomeningocele is the most common) is highly variable and depends upon ethnic and geographic factors. It usually ranges from one to five per 1000 live births. The highest rates are found in Ireland, Great Britain, Pakistan, India, and Egypt. Within the United States, rates are higher in the East and South compared to the West. In one series from Indiana, the overall incidence of isolated NTDs (excluding anencephaly) from 1988 to 1994 was one per 1000 births [17]. Girls are affected more often than boys.
INHERITANCE — The recurrence risk for any NTD was 1.5 to 3 percent in the United States when there was one affected sibling, based upon data from three large studies (show table 2) [18-20]. With two affected siblings, the risk was 5.7 percent in another United States study [21] and 12 percent in a British study [18].
PRENATAL DIAGNOSIS — Prenatal diagnosis is accomplished by maternal screening of serum alpha fetoprotein (AFP) levels and/or ultrasonography. (See "Prenatal screening and diagnosis of neural tube defects" and see "Ultrasound diagnosis of neural tube defects").
Maternal AFP screening — Maternal serum alpha fetoprotein screening for NTDs is performed in the second trimester. AFP screening is primarily intended for the detection of open spina bifida and anencephaly, but can also uncover several nonneural fetal abnormalities (eg, ventral wall defects, tumors, dermatologic disorders, congenital nephrosis, aneuploidy). Screening can be performed between 15 to 20 weeks of gestation; however, optimal detection of NTDs is between 16 and 18 weeks. It does not detect closed spina bifida.
Ultrasound findings — Sonographic fetal markers pathognomonic for neural tube defects include the lemon sign, the banana sign, ventriculomegaly, microcephaly, and obliteration of the cisterna magnum. The lemon sign refers to a concave shape of the frontal calvarium and the banana sign describes the posterior convexity of the cerebellum in the presence of spina bifida. These changes result from the Chiari malformation (ie, herniation of the cerebellum and brainstem through the foramen magnum) which is present in 95 percent of cases of spina bifida.
The normal fetal spine has three ossification centers within the fetal vertebrae. The centers of the neural arches are parallel, with gradual widening toward the fetal head and tapering at the sacrum. Spina bifida appears as widening of the ossification centers in the coronal plane and as a divergence of the ossification centers in the transverse plane. In addition, a cystic sac may be visualized if the fetus has a myelomeningocele.
CLINICAL FEATURES — The diagnosis of myelomeningocele is usually obvious at birth because of the grossly visible lesion (show figure 1). The vertebral defect involves the lumbar (thoracolumbar, lumbar, lumbosacral) regions (the last portion of the neural tube to close) in approximately 80 percent of cases, although any segment may be involved [22]. Many segments can be affected, and the entire spine distal to the most proximal malformed vertebra is often involved.
Neurologic deficits — The specific neurologic deficits depend upon the level of the lesion. In most affected patients, the entire spinal cord distal to the site of the lesion is nonfunctional. Motor and sensory deficits in the trunk and legs correspond to the segments that normally would have been innervated. The deficits usually are severe, resulting in complete paralysis and absence of sensation. The bladder and bowel are affected in nearly all patients, resulting in urinary and fecal incontinence.
Occasionally, the distal cord may retain some function, but the afferent pathways to the brain are disrupted. In this case, tendon reflexes or withdrawal to pain may be preserved, although voluntary control of movement and appreciation of pain are absent. A partially functioning segment of the spinal cord sometimes retains some central connections, resulting in voluntary control of isolated movements or the appreciation of sensation in part of the involved limbs. Aberrant connections in the involved spinal cord may result in unusual findings such as contraction of the contralateral limb when tendon reflexes are elicited.
Hydrocephalus — The majority of patients with myelomeningocele have hydrocephalus. The etiology is obstruction of fourth ventricular outflow or flow of CSF through the posterior fossa due to Chiari malformation or an associated aqueductal stenosis [23]. In one series of 156 children with myelomeningocele, 80 percent developed this disorder [24]. Hydrocephalus was due to aqueductal stenosis in 73 percent. Signs of hydrocephalus were present at birth in 15 percent of cases.
The likelihood of hydrocephalus depends upon the site of the lesion. Hydrocephalus is associated with approximately 90 percent of thoracolumbar, lumbar, and lumbosacral lesions, and approximately 60 percent of occipital, cervical, thoracic, or sacral lesions [22].
Ventricular dilatation is common at birth, often without increased head circumference or signs of increased intracranial pressure [25]. Hydrocephalus typically develops in the neonatal period after surgical repair of the back lesion. This is due to accumulation of excess CSF that previously was decompressed into the large sac or through a leaking myelomeningocele. Shunting is required in most patients.
Chiari malformation — The Chiari malformation is an anomaly of the hindbrain present in nearly all patients with thoracolumbar, lumbar, and lumbosacral myelomeningocele. It is the primary cause of the associated hydrocephalus. The major features of the anomaly are [22]:
Inferior displacement of the medulla and fourth ventricle into the upper cervical canal
Elongation and thinning of the upper medulla and lower pons and persistence of the embryonic flexure of these structures
Inferior displacement of the lower cerebellum through the foramen magnum in the upper cervical region
Bony defects of the foramen magnum, occiput, and upper cervical vertebrae
The malformation is classified into three types, according to the degree of caudal displacement. Type II, in which the fourth ventricle and lower medulla are displaced below the level of the foramen magnum, is the form that is usually associated with myelomeningocele.
Brain stem dysfunction due to the Chiari malformation occurs in some patients with myelomeningocele. This results in problems such as swallowing difficulties, vocal cord paresis causing stridor, and apneic episodes, and is associated with a high mortality rate [22]. Strabismus and facial weakness can also occur.
Other CNS anomalies — Other CNS anomalies often accompany myelomeningocele. In one report, neuropathologic examination was performed on 25 children with myelomeningocele, Chiari malformation, and hydrocephalus [26]. Cerebral cortical dysplasia occurred in 92 percent. The majority had neuronal heterotopias or polymicrogyria. Other abnormalities noted included cerebellar dysplasia (72 percent), hypoplasia or aplasia of cranial nerve nuclei (20 percent), fusion of the thalami (16 percent), agenesis of the corpus callosum (12 percent), and complete or partial agenesis of the olfactory tract and bulb (8 percent).
Scoliosis — Scoliosis occurs in most children with meningomyelocele who have lesions above L2 [22]. This complication is unusual when the lesion is below S1.
MANAGEMENT — Management of children with spina bifida should involve a multidisciplinary team with expertise in developmental pediatrics, neurosurgery, orthopedics, neurology, urology, and physical medicine and rehabilitation. Physical and occupational therapists, nutritionists, social workers, wound specialists, and psychologists are also helpful. This team of specialists works together to coordinate care and evaluate the patient's progress.
Delivery — If a prenatal diagnosis of myelomeningocele has been made, delivery should occur at a hospital with personnel experienced in the neonatal management of these infants [27]. Delivery before term may be indicated if rapidly increasing ventriculomegaly is observed and fetal lung maturity has been ********ed, otherwise, term delivery is preferable [27]. Sterile nonlatex gloves should be used during delivery to minimize the risk of latex sensitization [28].
Breech presenting fetuses are typically delivered by cesarean section. (See "Delivery of the fetus in breech presentation"). The optimal route of delivery of the vertex fetus is controversial, and no prospective randomized trials have been performed.
One study compared the outcome of 47 infants with a prenatal diagnosis of isolated myelomeningocele without severe hydrocephalus delivered by cesarean section before labor to a historic cohort of 113 infants with myelomeningocele diagnosed after delivery (35 delivered by cesarean section after a period of labor and 78 delivered vaginally) [29]. The level of paralysis at two years of age was approximately two segments lower in the group delivered by elective cesarean section without labor. However, it is possible that advances in neonatal care and prenatal diagnosis led to interventions in the delivery room that resulted in a better outcome in the study group. Several other retrospective studies, but not all [30], have not found a benefit of cesarean delivery, with or without labor, compared to vaginal birth [31-36].
Most centers deliver these infants by cesarean birth. Since data are inadequate to make a general recommendation about the optimal route of delivery, this decision should be individualized [27]. Future trials should address the effects of both route of delivery and labor on neuromuscular function.
Neonatal assessment — Immediately after birth, the lesion should be briefly assessed to note its location, size, and whether it is leaking CSF. Sterile non-latex gloves should be used. The defect should be covered with a sterile saline-soaked dressing. Large defects should also be covered by plastic wrap to prevent heat loss. In most cases, only the neurosurgeon should remove the dressing. The infant should be placed in a prone or lateral position to avoid pressure on the lesion.
The newborn should be evaluated thoroughly to detect associated abnormalities in order to make appropriate decisions regarding treatment [37]. The parents should be counseled regarding the infant's prognosis and participate in decisions regarding management [38].
The presence of the following should be noted:
Signs of hydrocephalus
Clubfeet
Flexion or extension contractures of hips, knees, and ankles
Kyphosis
Other abnormalities such as congenital heart disease; structural defects of the airway, gastrointestinal tract, ribs; developmental dysplasia of the hip; or ultrasound evidence of renal malformations such as hydronephrosis
Early complications such as CNS infection
A thorough neurologic examination should be performed. (See "Neurologic examination in children"). This should include:
Observation of spontaneous activity
Extent of muscle weakness and paralysis
Response to sensation
Deep tendon reflexes
Anocutaneous reflex (anal wink)
Surgical closure — The back lesion should be surgically closed within the first 24 to 48 hours after birth. This decreases the risk of CNS infection. Prophylaxis with broad spectrum antibiotics until the back is closed also reduces the risk of CNS infection. In a retrospective study of infants with back closure performed after 48 hours of age, ventriculitis occurred less with than without antibiotic prophylaxis (1 versus 19 percent) [39].
Hydrocephalus — Ventricular size should be evaluated soon after birth by ultrasound, CT, or MRI. Serial neuroimaging should be performed to identify the development of hydrocephalus. Progressive hydrocephalus should be treated by insertion of a ventriculoperitoneal shunt.
In some infants, simultaneous meningomyelocele repair and shunt placement may be appropriate. In a retrospective review, the frequency of CSF infection, shunt malfunction, and symptomatic Chiari malformation was similar with simultaneous and sequential repair and shunting [40]. The rate of wound leak was lower and hospital length of stay was shorter in the simultaneous group.
Orthopedic problems — Orthopedic management should be directed at correcting deformities, maintaining posture, and promoting ambulation if possible, so that patients can function at their maximum capability. Factors that predict an increased likelihood of walking ability are motor level and sitting balance [41].
Orthopedic deformities result from congenital skeletal anomalies that often involve the feet, knees, hips, and spine; unbalanced muscle action around joints; and fractures, which often affect the legs of paraplegic patients. In a review from Spain of 393 infants with myelodysplasia, hip dislocation and feet deformities occurred in 24 and 50 percent, respectively [42]. Scoliosis also is common. Management techniques that often improve function include the use of casting and corrective appliances, surgical procedures on soft tissue and bone, and the use of orthoses.
Fractures — Fractures of the lower extremities occur in approximately 30 percent of patients with meningomyelocoele [43]. They may develop without known traumatic injury or may be related to vigorous physical therapy. Factors that increase the risk of fracture include the lack of protective sensation of the leg, osteopenia, nonambulation, foot arthrodesis (fusion of the joint), and higher level of paralysis [43,44].
A fracture should be strongly suspected when a patient with myelodysplasia presents with a red, warm, and swollen limb. These clinical signs are sometimes confused with cellulitis or osteomyelitis because some children with diaphyseal and ****physeal fractures also have fever, elevated sedimentation rate, and leukocytosis [45], The diagnosis of fracture is confirmed with a radiograph of the limb.
Urinary tract complications — Nearly all patients with spina bifida have bladder dysfunction that can lead to deterioration of the upper urinary tract. The location of the spinal lesion or the neurologic examination do not predict the type of dysfunction. However, urinary continence with intermittent catheterization can be predicted by a positive anocutaneous reflex, which indicates a competent sphincter mechanism. In one report, continence was achieved in 26 of 29 patients (90 percent) with a positive reflex compared to 41 of 82 (50 percent) with a negative reflex [46]. Fewer patients with a positive reflex needed adjunctive surgery (7 versus 28 percent).
A baseline renal ultrasound and voiding cystourethrogram should be performed to identify patients at risk for upper tract deterioration. Function of the neurogenic bladder should be evaluated in affected newborns with a cystometrogram, which measures bladder capacity, compliance, voiding pressures, and the relationship between the detrusor and the urinary sphincter [47]. Vesicoureteral reflux may result from detrusor hyperreflexia or detrusor sphincter dyssynergy. In one report, urodynamic evaluation of 36 infants with myelodysplasia showed incoordination of the detrusor and external urethral sphincter, synergic activity of the sphincter, and no sphincter activity in 18, nine, and nine patients, respectively [48]. Infants with incoordination of the detrusor-external sphincter were at high risk for urinary tract deterioration. Of that group, 13 of 18 (72 percent) developed hydroureteronephrosis, compared to two of nine with synergy and one of nine with no sphincter activity.
Urologic function can deteriorate in affected children with normal urodynamic studies after surgical repair in the neonatal period [49]. Deterioration is due to spinal cord tethering, which is most likely to occur during the first six years of life. These children require close follow-up for the early detection and correction of tethered spinal cord (show figure 2).
Patients with vesicoureteral reflux should receive antibiotic prophylaxis, anticholinergic medication to lower detrusor filling and voiding pressures, and clean intermittent catheterization to prevent urinary tract deterioration [50,51]. The efficacy of this regimen was demonstrated in a sequential nonrandomized study that compared prophylactic (clean intermittent catheterization and oxybutynin) and expectant treatment in patients with these urodynamic findings [50]. During five years of follow-up, the upper urinary tract deteriorated less often in the treated group (8 versus 48 percent).
For an anticholinergic agent, oxybutynin syrup (Ditropan, 1 mg/mL) is used in a dose of 0.1 mg/kg PO three times a day for infants <12 months of age, and 1, 2, 3, or 4 mg/kg per dose three times a day for children one, two, or three years of age, respectively. For children 5 years old, we use oxybutynin tablets (Ditropan, 5 mg PO three times a day), or the extended release preparation (Ditropan XL, beginning with 5 mg PO daily and titrated to effect, with maximum dose 20 mg daily). An alternative drug is tolterodine (Detrol) in a dose of 1 to 2 mg PO twice a day or the long-acting preparation (Detrol LA), 2 to 4 mg PO daily.
Several surgical procedures are used to manage neurogenic bladder in patients with meningomyelocele. Ureteral reimplantation is sometimes performed in patients with persistent reflux and upper tract deterioration or with recurrent urinary tract infections in spite of clean intermittent catheterization and prophylactic antibiotics [52]. A vesicostomy is performed for bladder drainage in infants with high bladder pressure who continue to worsen while receiving clean intermittent catheterization and anticholinergic medication [53]. Vesicostomy is usually used for temporary diversion, but is a long-term option in patients unlikely to achieve continence [53,54].
The most common surgical approach is augmentation of the bladder [55]. In this procedure, a detubularized segment of intestine (ileum, colon, or stomach) is added to the bladder to increase capacity and lower pressure. The procedure usually results in the achievement of urinary continence. Linear growth and bone density are comparable in children with myelomeningocele with or without the procedure, although serum bicarbonate levels are lower and chloride levels are higher in those who have ileal, but not gastric augmentation [56]. Other complications include bladder calculi, bladder rupture, and excessive mucus in the urine that may lead to catheter obstruction [52].
Patients who are unable to catheterize their own urethra may benefit from a continent catheterizable channel (such as a Mitrofanoff or Monti ileovesicostomy). The new channel is constructed from appendix or bowel with a stoma placed at the level of the umbilicus or on the lower abdomen [57,58]. This more accessible location reduces the time required for clean intermittent catheterization, especially in females with lesions at the thoracic level. The most common complication is stenosis of the stoma at the level of the skin which may require dilation or surgical revision.
A surgical technique to bypass the neurologic defect through the microanastomosis of the fifth lumbar ventral root to the third sacral ventral root has been described [59]. Among 20 children with myelomeningocele who had this procedure, 17 achieved satisfactory bladder control and continence within 8 to 12 months after the procedure. These results await confirmation by other centers.
Neurogenic bowel — The innervation for internal and external sphincter control is at the level of S2 to S5. Thus, patients with meningomyelocoele may experience varying degrees of fecal incontinence. As children become preschool or school aged, fecal incontinence leads to embarrassment and social isolation and should be avoided.
Marvin A Fishman, MD
Grace B Villarreal, MD
UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on May 16, 2006. The next version of UpToDate (14.3) will be released in October 2006.
INTRODUCTION — Neural tube defects (NTDs) are the second only to cardiac malformations as the most prevalent congenital anomaly in the United States. Of these, myelomeningocele, anencephaly, and encephalocele are most common abnormalities. The clinical features, diagnosis, and management of myelomeningocele are reviewed here. Prenatal aspects and anencephaly and encephalocele and prevention of neural tube defects are discussed separately. (See "Prenatal screening and diagnosis of neural tube defects", see "Ultrasound diagnosis of neural tube defects" see "Anencephaly and encephalocele" and see "Prevention of neural tube defects").
EMBRYOLOGY OF NEURAL TUBE — The central nervous system (CNS) appears as a plate of thickened ectoderm called the neural plate at the beginning of the third week of embryonic life. The lateral edges of the neural plate become elevated to form the neural folds. These folds subsequently become further elevated, approach each other, and fuse to form the neural tube; the fusion begins in the cervical region and proceeds in both the cephalad and caudal directions. However, fusion is delayed at the cranial and caudal ends of the embryo so that the cranial and caudal neuropores form open communication between the lumen of the neural tube and the amniotic cavity. Closure of the cranial neuropore occurs on the 25th day after conception and closure of the caudal neuropore occurs approximately two days later [1]. Neural tube defects result from failure of the neural tube to close normally between 25 and 28 days after conception.
Myelomeningocele — Myelomeningocele (also known as myelocele and meningomyelocele), is due to failure of closure of the posterior neural tube. This leads to malformation of the vertebral column and spinal cord and other CNS anomalies. In severe forms, the neural plate appears as a raw, red, fleshy plaque through a defect in the vertebral column (known as spina bifida) and the integument. A protruding membranous sac containing meninges, CSF, nerve roots, and dysplastic spinal cord often protrudes through the defect. The majority of patients with myelomeningocele also have hydrocephalus and Chiari II malformations [2].
If disturbances occur during earlier stages of neural tube formation, canalization, and retrogressive differentiation, the resulting lesions are covered by skin. Approximately 10 percent of patients with spina bifida have a meningocele, in which only the meninges of the spinal cord herniate through the vertebral defect.
ETIOLOGY — The cause of NTDs is unknown. The majority are isolated malformations of multifactorial origin. NTDs also occur as part of syndromes, in association with chromosomal disorders, or as a result of an environmental exposure (show table 1) [3-9]. (See "Prenatal screening and diagnosis of neural tube defects").
Genetic factors — A genetic factor is suggested by the observations that NTDs have a high concordance rate in monozygotic twins, are more frequent among siblings, and are more common in females compared to males [10]. In addition, there is a high prevalence of karyotypic abnormalities among fetuses with NTDs, especially in the presence of other congenital anomalies. For example, a large study evaluating the frequency of aneuploidy in pregnancies with fetal NTDs found aneuploidy in 7 percent of affected cases [11]. The majority of the abnormal karyotypes were trisomies and most of the trisomic fetuses also had multiple congenital anomalies. A second series reported a similar rate (6.5 percent) of chromosomal abnormalities in fetuses with NTDs [12]. These data support the use of fetal karyotyping as an aid in diagnostic evaluation and recurrence risk counseling [11,12].
Folic acid deficiency — Adequate folate is critical for cell division due to its essential role in the synthesis of nucleic and certain amino acids. Folic acid deficiency has been implicated in the development of NTDs (folate sensitive NTDs) and folate supplementation has been shown to reduce the risk of NTDs. (See "Prevention of neural tube defects", section on Relationship between folate and NTDS).
Folic acid antagonists — Administration of folic acid antagonists (dihydrofolate reductase inhibitors and others) increases the risk of NTDs. In a large case-control study, the risk of NTDs (spina bifida, anencephaly, and encephalocele) was greater with than without exposure to folic acid antagonists (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) in the first or second month after the last menstrual period (adjusted odds ratio 2.8, 95% CI 1.7 to 4.6) [13]. The biologic mechanism for this association is largely unknown. (See "Risks associated with epilepsy and pregnancy" section on Antiepileptic drugs).
****bolic disorders — Genetic abnormalities involving the ****bolism of folate and homocysteine may account for some cases of NTDs [14]. These disorders may explain why supplementation with folic acid reduces but does not eliminate the risk of NTD. Genes affecting folate ****bolism include those encoding methylene tetrahydrofolate reductase and methylene tetrahydrofolate dehydrogenase. Those affecting homocysteine ****bolism include those encoding methionine synthase; its regulator, methionine synthase reductase; and cystathionine synthase.
Disruptive factors — Some cases of encephalocele may be due to disruptive factors. Encephalocele has been associated with amniotic bands, maternal hyperthermia between 20 and 28 days of gestation [15], and warfarin embryopathy [16].
INCIDENCE — The incidence of NTDs (of which myelomeningocele is the most common) is highly variable and depends upon ethnic and geographic factors. It usually ranges from one to five per 1000 live births. The highest rates are found in Ireland, Great Britain, Pakistan, India, and Egypt. Within the United States, rates are higher in the East and South compared to the West. In one series from Indiana, the overall incidence of isolated NTDs (excluding anencephaly) from 1988 to 1994 was one per 1000 births [17]. Girls are affected more often than boys.
INHERITANCE — The recurrence risk for any NTD was 1.5 to 3 percent in the United States when there was one affected sibling, based upon data from three large studies (show table 2) [18-20]. With two affected siblings, the risk was 5.7 percent in another United States study [21] and 12 percent in a British study [18].
PRENATAL DIAGNOSIS — Prenatal diagnosis is accomplished by maternal screening of serum alpha fetoprotein (AFP) levels and/or ultrasonography. (See "Prenatal screening and diagnosis of neural tube defects" and see "Ultrasound diagnosis of neural tube defects").
Maternal AFP screening — Maternal serum alpha fetoprotein screening for NTDs is performed in the second trimester. AFP screening is primarily intended for the detection of open spina bifida and anencephaly, but can also uncover several nonneural fetal abnormalities (eg, ventral wall defects, tumors, dermatologic disorders, congenital nephrosis, aneuploidy). Screening can be performed between 15 to 20 weeks of gestation; however, optimal detection of NTDs is between 16 and 18 weeks. It does not detect closed spina bifida.
Ultrasound findings — Sonographic fetal markers pathognomonic for neural tube defects include the lemon sign, the banana sign, ventriculomegaly, microcephaly, and obliteration of the cisterna magnum. The lemon sign refers to a concave shape of the frontal calvarium and the banana sign describes the posterior convexity of the cerebellum in the presence of spina bifida. These changes result from the Chiari malformation (ie, herniation of the cerebellum and brainstem through the foramen magnum) which is present in 95 percent of cases of spina bifida.
The normal fetal spine has three ossification centers within the fetal vertebrae. The centers of the neural arches are parallel, with gradual widening toward the fetal head and tapering at the sacrum. Spina bifida appears as widening of the ossification centers in the coronal plane and as a divergence of the ossification centers in the transverse plane. In addition, a cystic sac may be visualized if the fetus has a myelomeningocele.
CLINICAL FEATURES — The diagnosis of myelomeningocele is usually obvious at birth because of the grossly visible lesion (show figure 1). The vertebral defect involves the lumbar (thoracolumbar, lumbar, lumbosacral) regions (the last portion of the neural tube to close) in approximately 80 percent of cases, although any segment may be involved [22]. Many segments can be affected, and the entire spine distal to the most proximal malformed vertebra is often involved.
Neurologic deficits — The specific neurologic deficits depend upon the level of the lesion. In most affected patients, the entire spinal cord distal to the site of the lesion is nonfunctional. Motor and sensory deficits in the trunk and legs correspond to the segments that normally would have been innervated. The deficits usually are severe, resulting in complete paralysis and absence of sensation. The bladder and bowel are affected in nearly all patients, resulting in urinary and fecal incontinence.
Occasionally, the distal cord may retain some function, but the afferent pathways to the brain are disrupted. In this case, tendon reflexes or withdrawal to pain may be preserved, although voluntary control of movement and appreciation of pain are absent. A partially functioning segment of the spinal cord sometimes retains some central connections, resulting in voluntary control of isolated movements or the appreciation of sensation in part of the involved limbs. Aberrant connections in the involved spinal cord may result in unusual findings such as contraction of the contralateral limb when tendon reflexes are elicited.
Hydrocephalus — The majority of patients with myelomeningocele have hydrocephalus. The etiology is obstruction of fourth ventricular outflow or flow of CSF through the posterior fossa due to Chiari malformation or an associated aqueductal stenosis [23]. In one series of 156 children with myelomeningocele, 80 percent developed this disorder [24]. Hydrocephalus was due to aqueductal stenosis in 73 percent. Signs of hydrocephalus were present at birth in 15 percent of cases.
The likelihood of hydrocephalus depends upon the site of the lesion. Hydrocephalus is associated with approximately 90 percent of thoracolumbar, lumbar, and lumbosacral lesions, and approximately 60 percent of occipital, cervical, thoracic, or sacral lesions [22].
Ventricular dilatation is common at birth, often without increased head circumference or signs of increased intracranial pressure [25]. Hydrocephalus typically develops in the neonatal period after surgical repair of the back lesion. This is due to accumulation of excess CSF that previously was decompressed into the large sac or through a leaking myelomeningocele. Shunting is required in most patients.
Chiari malformation — The Chiari malformation is an anomaly of the hindbrain present in nearly all patients with thoracolumbar, lumbar, and lumbosacral myelomeningocele. It is the primary cause of the associated hydrocephalus. The major features of the anomaly are [22]:
Inferior displacement of the medulla and fourth ventricle into the upper cervical canal
Elongation and thinning of the upper medulla and lower pons and persistence of the embryonic flexure of these structures
Inferior displacement of the lower cerebellum through the foramen magnum in the upper cervical region
Bony defects of the foramen magnum, occiput, and upper cervical vertebrae
The malformation is classified into three types, according to the degree of caudal displacement. Type II, in which the fourth ventricle and lower medulla are displaced below the level of the foramen magnum, is the form that is usually associated with myelomeningocele.
Brain stem dysfunction due to the Chiari malformation occurs in some patients with myelomeningocele. This results in problems such as swallowing difficulties, vocal cord paresis causing stridor, and apneic episodes, and is associated with a high mortality rate [22]. Strabismus and facial weakness can also occur.
Other CNS anomalies — Other CNS anomalies often accompany myelomeningocele. In one report, neuropathologic examination was performed on 25 children with myelomeningocele, Chiari malformation, and hydrocephalus [26]. Cerebral cortical dysplasia occurred in 92 percent. The majority had neuronal heterotopias or polymicrogyria. Other abnormalities noted included cerebellar dysplasia (72 percent), hypoplasia or aplasia of cranial nerve nuclei (20 percent), fusion of the thalami (16 percent), agenesis of the corpus callosum (12 percent), and complete or partial agenesis of the olfactory tract and bulb (8 percent).
Scoliosis — Scoliosis occurs in most children with meningomyelocele who have lesions above L2 [22]. This complication is unusual when the lesion is below S1.
MANAGEMENT — Management of children with spina bifida should involve a multidisciplinary team with expertise in developmental pediatrics, neurosurgery, orthopedics, neurology, urology, and physical medicine and rehabilitation. Physical and occupational therapists, nutritionists, social workers, wound specialists, and psychologists are also helpful. This team of specialists works together to coordinate care and evaluate the patient's progress.
Delivery — If a prenatal diagnosis of myelomeningocele has been made, delivery should occur at a hospital with personnel experienced in the neonatal management of these infants [27]. Delivery before term may be indicated if rapidly increasing ventriculomegaly is observed and fetal lung maturity has been ********ed, otherwise, term delivery is preferable [27]. Sterile nonlatex gloves should be used during delivery to minimize the risk of latex sensitization [28].
Breech presenting fetuses are typically delivered by cesarean section. (See "Delivery of the fetus in breech presentation"). The optimal route of delivery of the vertex fetus is controversial, and no prospective randomized trials have been performed.
One study compared the outcome of 47 infants with a prenatal diagnosis of isolated myelomeningocele without severe hydrocephalus delivered by cesarean section before labor to a historic cohort of 113 infants with myelomeningocele diagnosed after delivery (35 delivered by cesarean section after a period of labor and 78 delivered vaginally) [29]. The level of paralysis at two years of age was approximately two segments lower in the group delivered by elective cesarean section without labor. However, it is possible that advances in neonatal care and prenatal diagnosis led to interventions in the delivery room that resulted in a better outcome in the study group. Several other retrospective studies, but not all [30], have not found a benefit of cesarean delivery, with or without labor, compared to vaginal birth [31-36].
Most centers deliver these infants by cesarean birth. Since data are inadequate to make a general recommendation about the optimal route of delivery, this decision should be individualized [27]. Future trials should address the effects of both route of delivery and labor on neuromuscular function.
Neonatal assessment — Immediately after birth, the lesion should be briefly assessed to note its location, size, and whether it is leaking CSF. Sterile non-latex gloves should be used. The defect should be covered with a sterile saline-soaked dressing. Large defects should also be covered by plastic wrap to prevent heat loss. In most cases, only the neurosurgeon should remove the dressing. The infant should be placed in a prone or lateral position to avoid pressure on the lesion.
The newborn should be evaluated thoroughly to detect associated abnormalities in order to make appropriate decisions regarding treatment [37]. The parents should be counseled regarding the infant's prognosis and participate in decisions regarding management [38].
The presence of the following should be noted:
Signs of hydrocephalus
Clubfeet
Flexion or extension contractures of hips, knees, and ankles
Kyphosis
Other abnormalities such as congenital heart disease; structural defects of the airway, gastrointestinal tract, ribs; developmental dysplasia of the hip; or ultrasound evidence of renal malformations such as hydronephrosis
Early complications such as CNS infection
A thorough neurologic examination should be performed. (See "Neurologic examination in children"). This should include:
Observation of spontaneous activity
Extent of muscle weakness and paralysis
Response to sensation
Deep tendon reflexes
Anocutaneous reflex (anal wink)
Surgical closure — The back lesion should be surgically closed within the first 24 to 48 hours after birth. This decreases the risk of CNS infection. Prophylaxis with broad spectrum antibiotics until the back is closed also reduces the risk of CNS infection. In a retrospective study of infants with back closure performed after 48 hours of age, ventriculitis occurred less with than without antibiotic prophylaxis (1 versus 19 percent) [39].
Hydrocephalus — Ventricular size should be evaluated soon after birth by ultrasound, CT, or MRI. Serial neuroimaging should be performed to identify the development of hydrocephalus. Progressive hydrocephalus should be treated by insertion of a ventriculoperitoneal shunt.
In some infants, simultaneous meningomyelocele repair and shunt placement may be appropriate. In a retrospective review, the frequency of CSF infection, shunt malfunction, and symptomatic Chiari malformation was similar with simultaneous and sequential repair and shunting [40]. The rate of wound leak was lower and hospital length of stay was shorter in the simultaneous group.
Orthopedic problems — Orthopedic management should be directed at correcting deformities, maintaining posture, and promoting ambulation if possible, so that patients can function at their maximum capability. Factors that predict an increased likelihood of walking ability are motor level and sitting balance [41].
Orthopedic deformities result from congenital skeletal anomalies that often involve the feet, knees, hips, and spine; unbalanced muscle action around joints; and fractures, which often affect the legs of paraplegic patients. In a review from Spain of 393 infants with myelodysplasia, hip dislocation and feet deformities occurred in 24 and 50 percent, respectively [42]. Scoliosis also is common. Management techniques that often improve function include the use of casting and corrective appliances, surgical procedures on soft tissue and bone, and the use of orthoses.
Fractures — Fractures of the lower extremities occur in approximately 30 percent of patients with meningomyelocoele [43]. They may develop without known traumatic injury or may be related to vigorous physical therapy. Factors that increase the risk of fracture include the lack of protective sensation of the leg, osteopenia, nonambulation, foot arthrodesis (fusion of the joint), and higher level of paralysis [43,44].
A fracture should be strongly suspected when a patient with myelodysplasia presents with a red, warm, and swollen limb. These clinical signs are sometimes confused with cellulitis or osteomyelitis because some children with diaphyseal and ****physeal fractures also have fever, elevated sedimentation rate, and leukocytosis [45], The diagnosis of fracture is confirmed with a radiograph of the limb.
Urinary tract complications — Nearly all patients with spina bifida have bladder dysfunction that can lead to deterioration of the upper urinary tract. The location of the spinal lesion or the neurologic examination do not predict the type of dysfunction. However, urinary continence with intermittent catheterization can be predicted by a positive anocutaneous reflex, which indicates a competent sphincter mechanism. In one report, continence was achieved in 26 of 29 patients (90 percent) with a positive reflex compared to 41 of 82 (50 percent) with a negative reflex [46]. Fewer patients with a positive reflex needed adjunctive surgery (7 versus 28 percent).
A baseline renal ultrasound and voiding cystourethrogram should be performed to identify patients at risk for upper tract deterioration. Function of the neurogenic bladder should be evaluated in affected newborns with a cystometrogram, which measures bladder capacity, compliance, voiding pressures, and the relationship between the detrusor and the urinary sphincter [47]. Vesicoureteral reflux may result from detrusor hyperreflexia or detrusor sphincter dyssynergy. In one report, urodynamic evaluation of 36 infants with myelodysplasia showed incoordination of the detrusor and external urethral sphincter, synergic activity of the sphincter, and no sphincter activity in 18, nine, and nine patients, respectively [48]. Infants with incoordination of the detrusor-external sphincter were at high risk for urinary tract deterioration. Of that group, 13 of 18 (72 percent) developed hydroureteronephrosis, compared to two of nine with synergy and one of nine with no sphincter activity.
Urologic function can deteriorate in affected children with normal urodynamic studies after surgical repair in the neonatal period [49]. Deterioration is due to spinal cord tethering, which is most likely to occur during the first six years of life. These children require close follow-up for the early detection and correction of tethered spinal cord (show figure 2).
Patients with vesicoureteral reflux should receive antibiotic prophylaxis, anticholinergic medication to lower detrusor filling and voiding pressures, and clean intermittent catheterization to prevent urinary tract deterioration [50,51]. The efficacy of this regimen was demonstrated in a sequential nonrandomized study that compared prophylactic (clean intermittent catheterization and oxybutynin) and expectant treatment in patients with these urodynamic findings [50]. During five years of follow-up, the upper urinary tract deteriorated less often in the treated group (8 versus 48 percent).
For an anticholinergic agent, oxybutynin syrup (Ditropan, 1 mg/mL) is used in a dose of 0.1 mg/kg PO three times a day for infants <12 months of age, and 1, 2, 3, or 4 mg/kg per dose three times a day for children one, two, or three years of age, respectively. For children 5 years old, we use oxybutynin tablets (Ditropan, 5 mg PO three times a day), or the extended release preparation (Ditropan XL, beginning with 5 mg PO daily and titrated to effect, with maximum dose 20 mg daily). An alternative drug is tolterodine (Detrol) in a dose of 1 to 2 mg PO twice a day or the long-acting preparation (Detrol LA), 2 to 4 mg PO daily.
Several surgical procedures are used to manage neurogenic bladder in patients with meningomyelocele. Ureteral reimplantation is sometimes performed in patients with persistent reflux and upper tract deterioration or with recurrent urinary tract infections in spite of clean intermittent catheterization and prophylactic antibiotics [52]. A vesicostomy is performed for bladder drainage in infants with high bladder pressure who continue to worsen while receiving clean intermittent catheterization and anticholinergic medication [53]. Vesicostomy is usually used for temporary diversion, but is a long-term option in patients unlikely to achieve continence [53,54].
The most common surgical approach is augmentation of the bladder [55]. In this procedure, a detubularized segment of intestine (ileum, colon, or stomach) is added to the bladder to increase capacity and lower pressure. The procedure usually results in the achievement of urinary continence. Linear growth and bone density are comparable in children with myelomeningocele with or without the procedure, although serum bicarbonate levels are lower and chloride levels are higher in those who have ileal, but not gastric augmentation [56]. Other complications include bladder calculi, bladder rupture, and excessive mucus in the urine that may lead to catheter obstruction [52].
Patients who are unable to catheterize their own urethra may benefit from a continent catheterizable channel (such as a Mitrofanoff or Monti ileovesicostomy). The new channel is constructed from appendix or bowel with a stoma placed at the level of the umbilicus or on the lower abdomen [57,58]. This more accessible location reduces the time required for clean intermittent catheterization, especially in females with lesions at the thoracic level. The most common complication is stenosis of the stoma at the level of the skin which may require dilation or surgical revision.
A surgical technique to bypass the neurologic defect through the microanastomosis of the fifth lumbar ventral root to the third sacral ventral root has been described [59]. Among 20 children with myelomeningocele who had this procedure, 17 achieved satisfactory bladder control and continence within 8 to 12 months after the procedure. These results await confirmation by other centers.
Neurogenic bowel — The innervation for internal and external sphincter control is at the level of S2 to S5. Thus, patients with meningomyelocoele may experience varying degrees of fecal incontinence. As children become preschool or school aged, fecal incontinence leads to embarrassment and social isolation and should be avoided.