Neural tube defects: Prenatal sonographic diagnosis

INTRODUCTION — Ultrasound examination is an effective modality for prenatal diagnosis of neural tube defects (NTDs), which are the second most frequent category of congenital anomalies after congenital heart disease. Imaging has largely replaced measurement of maternal serum alpha-fetoprotein (MSAFP) for NTD screening.

An accurate diagnosis depends upon correctly imaging the fetal central nervous system (CNS), correctly interpreting the images, thoroughly evaluating the fetus for associated malformations (which are often present), and diagnostic genetic testing. Early accurate prenatal diagnosis allows parents time to become informed about the fetal disorder, its prognosis, and their options, including reproductive decision-making regarding pregnancy termination or planning for the birth of an anomalous child (eg, management of the pregnancy, possible in utero intervention, route of delivery, delivery site, newborn care).

The sonographic diagnosis of selected, more common, primarily open NTDs will be discussed here. Related issues are reviewed separately:

●Prenatal screening for NTDs, diagnostic evaluation, and pregnancy management, including in utero treatment (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management".)

●Prevention of NTDs (See "Folic acid supplementation in pregnancy".)

●Isolated fetal ventriculomegaly (See "Fetal cerebral ventriculomegaly".)

●Sonographic diagnosis of fetal CNS anomalies other than NTDs and ventriculomegaly (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly".)

GENERAL PRINCIPLES OF FETAL NEUROIMAGING

●Ultrasonography is the modality of choice in the evaluation of a fetus at risk for an NTD, given its high detection rates – Clinical evidence supports the use of first-trimester (at 11 to 14 weeks gestation) and routine second-trimester (18 to 22 weeks gestation) ultrasound examination for screening and diagnosis of fetal NTDs [1]. Structures that should be assessed when an NTD is detected include the presence/absence of the cranium, hindbrain herniation, ventriculomegaly, vertebral lesions (and level of any lesions), lower limb deformities, and associated anomalies.

●Knowledge of normal CNS anatomy across gestation is essential – A thorough understanding of the normal sonographic appearance of the CNS across gestation is essential for accurate diagnosis since the presence or absence of a structure may be interpreted as normal or abnormal depending upon the gestational age of the fetus. For example, a sonogram of the fetal brain at 14 weeks of gestation cannot detect agenesis of the corpus callosum because this structure does not become sonographically apparent until 18 to 20 weeks and does not acquire its final form until 28 to 30 weeks. Ossification of the cranium begins at about 10 weeks of gestation, with extensive ossification of both parietal bones by 14 weeks, thus anencephaly can be diagnosed at the time of nuchal translucency screening.

●Open versus closed NTDs – Closed or occult NTDs may go undetected, even in the newborn.

●Role of three-dimensional ultrasound – Three-dimensional ultrasound plays an important role in the evaluation of brain anomalies since it can further characterize these defects. Multiplanar imaging of the brain and use of a variety of display modalities (eg, tomographic imaging, inversion, maximum-mode, surface rendering, volume scanning) allow the sonologist to obtain planes and sections not easily obtainable with conventional two-dimensional sonography (image 1).

The pediatric neurologist or neurosurgeon can use this additional information when counseling parents about prognosis and clinical management options.

●Role of MRI – Very early in the pregnancy, ultrasound may provide more information about the CNS than magnetic resonance imaging (MRI), but MRI may be superior to ultrasound for evaluating the brain parenchyma in the late-second and third trimesters.

MRI is used in situations where the CNS malformation is not clear and detailed assessment of the CNS is required for diagnostic or management counselling. For example, MRI is better for visualizing some brain malformations, such as migrational anomalies, which are not seen well on ultrasound. For patients considering fetal surgery for myelomeningocele, MRI is typically utilized to assess for associated abnormalities and follow improvements in the Chiari malformation [2]. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Consider fetal surgery for myelomeningocele repair'.)

●Genetic counseling and testing – When imaging detects an NTD, genetic counseling is useful to discuss the risk of a genetic abnormality, options for noninvasive and invasive diagnostic testing (eg, cell-free DNA screening, microarray, fetal exome sequencing), post-test interpretation of results (fetal prognosis, recurrence risk in future pregnancies), and reproductive options.

DIAGNOSIS OF SELECTED NTDS

Exencephaly-anencephaly sequence

Background — Exencephaly-anencephaly sequence refers to a spectrum of anomalies in which initially there is failure of the anterior neuropore to close at approximately 10 to 20 postovulatory days, resulting in the formation of a "relatively" normal brain with absence of meninges and a normal calvarium (ie, exencephaly) [3-9]. The effects of mechanical and amniotic fluid influences on the exposed brain cause it to degenerate, leading to anencephaly (image 2) [10].

Anencephaly was the most common NTD prior to the era of folic acid food fortification/supplementation and prenatal screening, occurring in approximately 1 per 1000 births [11,12]. The incidence has fallen dramatically since the introduction of these practices [13]. (See "Folic acid supplementation in pregnancy".)

Prenatal diagnosis — A direct sonographic sign of exencephaly-anencephaly sequence is an abnormally shaped head with absence of the cranium and a significant amount of brain tissue exposed. An indirect sign is the presence of low-level echogenic, particulate matter in the amniotic fluid. This results from "rubbing off" of the exposed neural tissue/angiomatous stroma [14]. Measurement of the crown-chin length and the ratio of the crown-chin to crown-rump length (CRL) at 10 to 14 postmenstrual weeks is also useful in the early recognition of the abnormality (table 1) [15]. A fetus with a shorter than expected CRL after 10 weeks of gestation should also be studied carefully for absence of an ossified skull as the potential cause. At this stage, the exencephalic fetus has an abnormal head shape with sonolucent spaces within the exposed and disintegrating brain. The outer shape of the exposed brain may be bilobed since the exposed two hemispheres fall to the side; this appearance has been called "Mickey Mouse" head (image 3). Over time, the exposed brain develops a heterogeneous appearance (image 4) and then disappears, resulting in the typical appearance of anencephaly.

The fetus affected with the exencephaly-anencephaly sequence can be definitively identified by the 12^th postmenstrual week by transvaginal ultrasound, although in some cases this diagnosis has been made as early as 9 to 10 postmenstrual weeks [16,17]. Early diagnosis can be made if the cranium is examined carefully at the time of the nuchal translucency measurement, which is performed when the CRL is 36 to 84 mm (corresponding to approximately 10 to 14 weeks of gestation) [18].

In the second and third trimesters, diagnosis of anencephaly is made when the skull is absent above the orbits anteriorly and above the cervical spine posteriorly (image 5). The cerebrum, cerebellum, and basal ganglia are also absent, but a variable amount of disorganized echogenic brain tissue (sometimes called area cerebrovasculosa) may remain and mostly consists of brainstem [19]. The fetal face from the orbits to the chin is usually normal. The base of the skull is present but thick and flattened.

Associated findings

●Polyhydramnios develops in up to 50 percent of the cases during the late-second and the third trimester because of decreased fetal swallowing [4,20-22]. Amniotic fluid volume is normal in the first trimester.

●Craniorachischisis (congenital incomplete closure of the skull and spine) is observed in less than 10 percent of cases [22]. Other malformations that have been described include cleft lip and palate, cardiac anomalies, diaphragmatic hernia, abdominal wall defects, and renal, skeletal, and gastrointestinal anomalies.

●Aneuploidy is present about 2 percent of cases, including the common trisomies (21, 18, and 13), triploidy, and some genetic deletions and duplications [23].

●Fetal activity is not significantly impaired; however, the quality of fetal movement is often different from that in normal fetuses [24-28] and the fetus may not respond to vibroacoustic stimulation [29,30].

●Maternal serum alpha-fetoprotein (MSAFP) levels are highly elevated.

Prognosis — Most pregnancies are terminated upon prenatal diagnosis given the uniformly lethal prognosis [31,32]. In ongoing pregnancies, most anencephalic fetuses are stillborn (antepartum or intrapartum death) or die shortly after birth, but some have been reported to survive as long as 28 days [33,34]. Preterm labor and birth may occur from uterine overdistention related to polyhydramnios or the pregnancy may extend post term because absence of fetal brain precludes some of the normal pathways involved in the fetal component of initiation of labor [35].

Parental counseling and management of the anencephalic newborn are reviewed in detail separately. (See "Anencephaly".)

Spinal dysraphism

Background — Spinal dysraphism (also called spina bifida) refers to protrusion of the spinal contents through a bony defect in the spine (image 6A-B). Approximately 80 percent occur in the lumbar, thoracolumbar, or lumbosacral areas of the spine, with the remainder in the cervical and sacral areas [36]. Myelomeningocele and myelocele are two most common types of open spinal dysraphism and develop similarly:

●Myelomeningocele is a bulging defect in which the elevated neural plate and meninges protrude through a defect of the vertebral arches and are contiguous laterally with the subcutaneous tissue (image 7).

●Myelocele is a midline plaque of neural tissue (neural placode) that protrudes through a defect of the vertebral arches and is flush with the fetal surface and open (not covered by skin).

Closed spinal dysraphism (also referred to as spina bifida occulta) occurs in approximately 10 to 15 percent of cases of spinal dysraphism. The spinal anomaly is covered by skin or a thick membrane; therefore, the neural tissue is not exposed and is not associated with elevated MSAFP levels. This condition is typically asymptomatic if only the spinous process and neural arch of the vertebrae are affected. At times spina bifida occulta is used to include other conditions such as tethered cord and lipomyelomeningocele, which can be associated with significant neurologic dysfunction. (See "Closed spinal dysraphism: Pathogenesis and types" and "Closed spinal dysraphism: Clinical manifestations, diagnosis, and management".)

Prenatal diagnosis — Diagnosis is typically in the second trimester. Second-trimester sonography has 97 to 98 percent sensitivity for detecting spinal dysraphism and essentially 100 percent specificity (ie, no false positives) in populations at high risk [37-39]. It should be suspected in fetuses with loss of the convex outward shape of the frontal bones with mild flattening (lemon sign), anterior curvature of the cerebellum around the brainstem (banana sign) likely due to leakage of spinal fluid from the open spinal defect, or hydrocephaly, which are well-established cranial sonographic markers of the anomaly (image 8A-B) [40,41]. The banana sign is essentially 100 percent specific for spinal dysraphism, whereas the lemon sign can be seen in normal fetuses.

When any of these cranial findings are observed, a detailed ultrasound examination of the spine in the sagittal, transverse, and coronal planes is indicated. In spinal dysraphism, the sagittal view shows irregularities of the bony spine, a bulging within the posterior contour of the fetal back, or obvious disruption of the fetal skin contours. The coronal plane of the affected bony segment shows widening of the ossification centers replacing the normal parallel lines of the normal vertebral arches, and the transverse plane shows divergence of the ossification centers, resulting in U-shaped vertebrae. A cystic sac may be visualized if the fetus has a myelomeningocele (image 7 and image 6A and image 6B).

●Arnold-Chiari type II malformation – The Arnold-Chiari type II malformation refers downward displacement of inferior cerebellar vermis, cerebellar tonsils, and medulla through the foramen magnum into the upper cervical canal, typically in association with a myelomeningocele at the lumbosacral or occasionally a higher level of the spinal cord. Additional CNS anomalies are common. In a systematic review, the cranial findings included posterior fossa funneling/herniation of cerebellar vermis through the foramen magnum (96 percent), small transcerebellar diameter (82 to 96 percent), banana sign (50 to 100 percent), beaked tectum (65 percent), lemon sign (53 to 100 percent), small biparietal diameter and head circumference (<5^th percentile; 53 and 71 percent, respectively), ventriculomegaly (45 to 89 percent), abnormal pointed shape of the occipital horn (77 to 78 percent), thinning of the posterior cerebrum, perinodular heterotopia (11 percent), abnormal gyration (3 percent), corpus callosum disorders (60 percent), and midline interhemispheric cyst (42 percent) [41-43].

Spinal dysraphism may be detected between 11 and 14 weeks by noting irregularities of the bony spine or a bulging within the posterior contour of the fetal back (image 9) [44,45]. Abnormalities of the posterior half of the fetal brain, including absence of visualization of the intracranial translucency (image 10), nonvisualization of the cisterna magna, posterior shift of the brainstem toward the occipital bone, smaller than expected biparietal diameter, a ratio of brainstem (BS) diameter to brainstem to the occipital bone (BSOB) diameter (BS/BSOB) greater than one (image 11), have been described as early signs of open spinal dysraphism [46-56]. A second-trimester ultrasound scan is indicated to make the diagnosis or confirm a suspected diagnosis in the first trimester. The banana and lemon signs are generally absent or subtle in the first trimester [57,58].

Two new potential markers have also been described. The first is the "dry brain," in which the choroid plexus (CP) in an axial transventricular view of the head appears to fill the entire ventricular cavity with minimal or no cerebral spinal fluid present [55]. The dry brain has been evaluated by measuring the ratio of the length of the CP to the occipital frontal diameter (OFD) or the biparietal diameter (image 12). In the normal fetus, the ratio of CP area to head area and CP length to OFD decreased with increasing CRL, whereas both ratios increased in 88 percent of fetuses with open spina bifida, giving the appearance that the entire head was filled with CP with no cerebral spinal fluid. In all cases, the BS/BSOB ratio was also noted to be increased and the IT was not seen in about 60 percent. In a subsequent study of 3300 pregnancies in which 24 fetuses had open spina bifida, the optimal mean CP to OFD ratio resulted in a positive predictive value of 90.9 percent and a negative predictive value of 99.6 percent [59]. The second marker is the "crash sign," in which there is posterior displacement and deformation of the mesencephalon against the occipital bone in the axial ultrasound view (image 13). This has been reported in 90.6 percent of cases of open spina bifida [60]. Large prospective studies are necessary to ascertain the value of these new markers [57,58,61].

Associated findings — Potential associated findings include [19,62,63] (see "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications"):

●CNS – Relative microcephaly, agenesis of the corpus callosum, diastematomyelia (ie, longitudinal split in the spinal cord)

●Non-CNS – Scoliosis or kyphosis, hip deformities

●Progressive deterioration of leg movements, abnormal positioning of one or both feet (clubfoot)

●Genetic abnormalities (eg, trisomy 13 or 18), especially in the presence of other congenital anomalies

●MSAFP levels are highly elevated, except when the defect is covered by skin

Predicting functional outcome — Determining the level and extent of the spinal lesion is important because these features correlate with neurologic outcome; more severe neurologic dysfunction is associated with higher and larger lesions. This is done prenatally by identifying the level of the last thoracic rib, labeling that level T12, and counting up or down from that vertebra (image 1).

There are scant data regarding prognostically useful sonographic features of fetuses with NTDs [64-67]:

●Combined data from two series (n = 28 and 33 cases) showed that prenatal sonographic and postnatal assessment were concordant within one vertebral segment in 79 percent of patients [64], within two vertebral segments in 92 percent of patients, and within three vertebral segments in 100 percent of patients [65]. The latter study also found that:

•Lesion level was most predictive of ambulatory function. All infants with thoracic lesions or myeloschisis (spina bifida with cleft spinal cord) were nonambulatory upon assessment at age 1 to 5 years.

•Sonography was not useful for predicting future need for shunt placement, but almost all of the subjects eventually required this procedure.

•Lesion type was correctly identified sonographically in all cases.

This study did not evaluate postnatal urologic and bowel function and cognitive capacity, which are other important functional outcomes.

●Others have reported that prenatal sonographic lesion level predicted postnatal neuromuscular function "equal to or better than that expected" in 10 of 11 patients (91 percent) [68] or "equal to that expected" in 12 of 15 patients (80 percent) [66].

●The outcome of prenatally diagnosed myelomeningocele has also been correlated with findings on magnetic resonance imaging (MRI). A review of 36 pregnancies complicated by fetal myelomeningocele, referred for fetal MRI at mean gestational age 27±6 weeks, and followed postnatally at a spina bifida treatment center reported the following findings at follow-up at 2.4 to 5.1 years of age [69]:

•Higher lesion levels were associated with dysphagia: T-L2 (50 percent), L3-4 (45 percent), L5-S (13 percent).

•The absence of covering membrane was associated with scoliosis (36 versus 0 percent with membrane present) and with high-risk bladder dysfunction (71 versus 36 percent).

•Higher lesion level, larger segment span, and interpediculate distance greater than 10 mm were associated with full-time wheelchair use.

The postnatal care and prognosis of the newborn with myelomeningocele are reviewed in detail separately. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications" and "Myelomeningocele (spina bifida): Management and outcome".)

Cephalocele

Background — Cephaloceles are classified according to their contents and location. They are usually, but not exclusively, midline cranial defects through which the brain and/or meninges have herniated outside of the skull (image 14A-C and image 15 and image 16A-C). The occipital, frontal, parietal, orbital, nasal, or nasopharyngeal region of the head can be involved, but most occur posteriorly [70]. Cephaloceles caused by amniotic band sequence can involve any part of the skull. (See "Amniotic band sequence".)

Prenatal diagnosis — The typical sonographic appearance is a defect of the bony skull with a protruding sac-like structure. The sac may contain brain (encephalocele), anechoic cerebrospinal fluid (meningocele) (image 15) [71], or a combination of both (image 14A-C and image 16A-C) [72-76]. Encephalocele is much more common than meningocele. Approximately 80 percent are covered by skin or a thick membrane.

Cephalocele can be diagnosed as early as 11 to 14 weeks at the time of the nuchal translucency measurement [77-79]. The size of both the cranial defect and the cephalocele sac can vary widely (millimeters to many centimeters). If the defect is large, the head circumference and biparietal diameter can be significantly smaller than expected for the gestational age.

Associated findings

●Cephalocele usually occurs as an isolated lesion, but may be a part of a syndrome. Therefore, evaluation for the potential etiology and determination of the recurrence risk should include genetic counseling and testing. Genetic testing should not be limited to a conventional karyotype; microarray is preferable and in cases where microarray is normal, exome sequencing may be an option after consultation with a genetics expert.

●The classical triad of Meckel (or Meckel-Gruber) syndrome is occipital cephalocele (present in 80 percent), bilateral polycystic kidneys, and post-axial polydactyly [80,81]. These abnormalities may be difficult to visualize since renal dysfunction results in severe oligohydramnios. Prenatal diagnosis has been made in the first and early second trimesters [81-87]. Inheritance is autosomal recessive.

●Cephaloceles may be associated with ventriculomegaly, microcephaly, aneuploidy (trisomies 13, 18, and 21), intracranial malformations, spinal dysraphism, cleft palate, microphthalmia, tracheoesophageal fistula, and cardiac malformations [19,79].

●MSAFP levels are highly elevated, except when the defect is covered by scalp (which is common).

Prognosis — The prognosis depends on the location, size, content of the lesion, and associated malformations. Both fetal and newborn mortality are increased, particularly in fetuses with encephaloceles associated with other anomalies [70]. Preterm birth and fetal growth restriction may occur and are also associated with an increased risk of mortality. Neurodevelopmental disabilities are common in surviving children.

 The postnatal management and outcome of newborns with encephalocele are reviewed in detail separately. (See "Primary (congenital) encephalocele".)

Iniencephaly

Background — Iniencephaly is a rare, lethal developmental anomaly. Although it is not a true NTD, many textbooks list it in the CNS section. The malformation results from developmental arrest of the embryo during the third postmenstrual week. This results in persistence of embryonic cervical retroflexion and leads to failure of the neural groove to close in the area of the cervical spine or upper thorax [88-90].

Prenatal diagnosis — The sonographic diagnosis has been made as early as 12.5 to 13 postmenstrual weeks [73,91]. The three major diagnostic features are [88,89,91-95]:

●A defect in the occiput involving the foramen magnum.

●Retroflexion of the entire spine, which forces the fetus to look upwards with its occiput directed towards the lumbar region.

●Open spinal defects of variable degrees present in up to 50 percent of the cases [96].

Associated findings — Associated malformations occur in up to 84 percent of cases and include [88,92,93,97,98]:

●CNS – Hydrocephaly, microcephaly, ventricular atresia, holoprosencephaly, polymicrogyria, agenesis of the cerebellar vermis, occipital encephalocele

●Non-CNS – Diaphragmatic hernia, thoracic cage deformities, urinary tract anomalies, cleft lip and palate, omphalocele, and polyhydramnios

Prognosis — Due to the rare occurrence and the feasibility of first- and early second-trimester detection, fetuses with iniencephaly are rarely live born, but at least one live birth has been reported [99].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital malformations of the central nervous system".)

SUMMARY AND RECOMMENDATIONS

●Prevalence – Central nervous system (CNS) malformations are the second most frequent category of congenital anomaly, after congenital heart disease. (See 'Introduction' above.)

●Spinal dysraphism (spina bifida) – Spinal dysraphism or spina bifida refers to protrusion of the spinal contents through a bony defect in the spine. Hydrocephalus is usually present as well. Three-dimensional ultrasound examination may aid in diagnosis. Microarray should be offered given the high risk of aneuploidy. (See 'Spinal dysraphism' above.)

●Anencephaly – Anencephaly is a lethal abnormality in which a large part of the entire brain is absent, the fetal face from the orbits (with bulging eyeballs) to the chin is usually normal, and there is no skull above the orbits anteriorly and above the cervical spine posteriorly. Delivery is usually induced given the uniformly lethal prognosis. (See 'Exencephaly-anencephaly sequence' above.)

●Cephalocele – Cephaloceles (eg, encephalocele) are cranial defects through which the brain and/or meninges have herniated outside of the skull. Cephalocele usually occurs as an isolated lesion, but may be a part of a syndrome such as Meckel (or Meckel-Gruber) syndrome or due to amniotic bands. Three-dimensional ultrasound examination may aid in diagnosis. Microarray should be offered given the high risk of aneuploidy. (See 'Cephalocele' above.)