Version July 2025
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. Ultrasound 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), properly interpreting the images, thoroughly evaluating the fetus for associated anomalies (which are often present), and diagnostic genetic testing. Early accurate prenatal diagnosis allows the patient 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 affected child (eg, management of the pregnancy, possible in utero intervention, route and site of birth, 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 "Preconception and prenatal folic acid supplementation".)
●(See "Open spina bifida: In utero treatment and delivery considerations".)
●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 – Ultrasound is the modality of choice because of its safety, accessibility, and high sensitivity in the first trimester (at 11 to 14 weeks gestation) and especially in the second trimester (18 to 22 weeks gestation) [1-4]. Specific structures that should be assessed when an NTD is suspected include the location and extent of the any lesions; the presence/absence of hindbrain herniation, ventriculomegaly, and lower limb deformities; and associated anomalies in other organ systems.
●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 or earlier if transvaginal sonography is performed.
●Limitations – 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 CNS 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 additional information about CNS anatomy when counseling parents about prognosis and clinical management options.
●Role of MRI – Very early in the pregnancy high-frequency transvaginal sonography 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 abnormality is not clear and detailed assessment of the CNS is required for diagnosis or management. For example, MRI is better for visualizing some brain abnormalities, 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 [5]. (See "Open spina bifida: In utero treatment and delivery considerations".)
●Genetic counseling and testing – When an NTD is diagnosed, genetic counseling is useful to discuss the risk of a genetic abnormality, options for noninvasive and invasive diagnostic testing (eg, cell-free DNA screening, chromosomal microarray, fetal exome or whole genome sequencing), post-test interpretation of results (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 the anterior neuropore fails to close at approximately 10 to 20 postovulatory days, resulting in formation of a "relatively" normal brain with absence of meninges and a normal calvarium (ie, exencephaly) [6-12]. Subsequently, mechanical and amniotic fluid effects on the exposed brain cause it to degenerate, leading to anencephaly (image 2) [13].
Before the era of folic acid food fortification/supplementation and prenatal NTD screening, anencephaly was the most common NTD, occurring in approximately 1 per 1000 births [14,15]. However, the incidence has fallen dramatically since the introduction of these practices [16]. (See "Preconception and prenatal folic acid supplementation".)
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 exposed brain tissue. An indirect sign is the presence of low-level echogenic, particulate matter in the amniotic fluid, which derives from the exposed neural tissue/angiomatous stroma "rubbing off" [17]. 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) [18]. A fetus with a shorter than expected CRL after 10 weeks of gestation should also be studied carefully for absence of an ossified cranium 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 12th postmenstrual week by transvaginal ultrasound, although in some cases this diagnosis has been made as early as 9 to 10 postmenstrual weeks [19,20]. 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 45 to 84 mm (corresponding to approximately 11 to 14 weeks of gestation) [21].
In the second and third trimesters, diagnosis of anencephaly is made when the cranium 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 [22]. 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 cases during the late-second and the third trimester because of decreased fetal swallowing [7,23-25]. 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 [25]. Other malformations that have been described include cleft lip and palate, cardiac anomalies, diaphragmatic hernia, abdominal wall defects, and kidney, 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 [2].
●Fetal activity is not significantly impaired; however, the quality of fetal movement is often different from that in fetuses without neuromuscular disorders [26-30] and the fetus may not respond to vibroacoustic stimulation [31,32].
●Maternal serum alpha-fetoprotein (MSAFP) levels are highly elevated, if obtained.
Prognosis — Most pregnancies are terminated upon prenatal diagnosis given the uniformly lethal prognosis [33,34]. 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 [35,36]. Preterm labor and birth may occur from uterine overdistention related to polyhydramnios, if present, or the pregnancy may extend postterm because absence of fetal brain precludes some of the normal neuroendocrine pathways involved in the fetal component of initiation of labor [37].
Maternal 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 [38]. Open spinal dysraphism (ie, not covered by skin or a thick membrane) is more common than closed (ie, covered by skin or a thick membrane). Myelomeningocele and myelocele are the most common types of open spinal dysraphism and develop similarly:
●In myelomeningocele, a sac containing the neural placode, CSF, and meninges protrudes through a defect of the vertebral arches, extends through the intervening tissue, and bulges beyond the fetal surface (image 7).
●In myelocele, a midline plaque of neural tissue protrudes through a defect of the vertebral arches and extends through the intervening tissue until it is flush with the fetal surface (image 8). It is not covered by skin or contained by a sac and does not bulge.
Closed spinal dysraphism (also called spina bifida occulta) accounts for approximately 10 to 15 percent of cases of spinal dysraphism. Closed spinal dysraphism is typically asymptomatic if only the spinous process and neural arch of the vertebrae are affected (ie, neural placode, CSF, and meninges are in their normal location). The term spina bifida occulta may be 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".)
In meningocele, a sac containing only CSF and the meninges protrudes through a defect of the vertebral arches and extends through the intervening tissue. Meningocele may be open or closed.
Prenatal diagnosis
●First trimester – 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) [39,40]. Abnormalities of the posterior half of the fetal brain, including absence of visualization of the intracranial translucency (also known as the fourth ventricle) (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 [41-51]. 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 [52,53].
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 [50]. 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 [54]. 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 [55]. Large prospective studies are necessary to ascertain the value of these new markers [52,53,56].
●Second trimester – Spinal dysraphism is typically diagnosed in the second trimester at the routine fetal anatomic survey. 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 [57-59]. 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 14A-B) [60,61]. 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).
Associated findings — Potential findings associated with open NTDs include [22,62,63] (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)
The Arnold-Chiari type II malformation refers to 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 (<5th 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) [61,64,65].
●Non-CNS – Scoliosis or kyphosis, hip deformities
●Progressive reduction in leg movements
●Abnormal positioning of one or both feet (clubfoot)
●Genetic abnormalities (eg, trisomy 13 or 18), especially when the NTD is associated with other congenital anomalies
●Highly elevated MSAFP levels
Predicting functional outcome — Determining the level and extent of the spinal lesion is important because these features correlate with postnatal neurologic outcome; higher and larger lesions are associated with more severe neurologic dysfunction. This is performed 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 limited data regarding prognostically useful sonographic features in fetuses with NTDs [66-69]:
●Combined data from a total of 61 cases in two series showed that prenatal sonographic and postnatal assessment were concordant within one vertebral segment in 79 percent of cases [66], within two vertebral segments in 92 percent of cases, and within three vertebral segments in 100 percent of cases [67]. One of the studies also found that [67]:
•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 the procedure was eventually required in almost all cases.
•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) [70] or "equal to that expected" in 12 of 15 patients (80 percent) [68].
●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 [71]:
•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 15A-C and image 16 and image 17A-C). The occipital, frontal, parietal, orbital, nasal, or nasopharyngeal cephalic region can be involved, but most occur posteriorly [72]. Cephaloceles caused by amniotic band sequence can involve any part of the cranium. (See "Amniotic band sequence".)
Prenatal diagnosis — The typical sonographic appearance is a defect of the skull with a protruding sac-like structure. The sac may contain brain (encephalocele), anechoic cerebrospinal fluid (meningocele) (image 16) [73], or a combination of both (image 15A-C and image 17A-C) [74-78]. 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 [79-81]. 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, genetic counseling and testing should be offered to evaluate the potential etiology and determine the recurrence risk. Genetic testing should not be limited to a karyotype; chromosomal microarray is preferable and in cases where microarray is normal, exome or genome 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 [82,83]. These abnormalities may be difficult to visualize since kidney dysfunction results in severe oligohydramnios. Prenatal diagnosis has been made in the first and early second trimesters [83-89]. Inheritance is autosomal recessive.
●Cephaloceles may be associated with ventriculomegaly, microcephaly, aneuploidy (trisomies 13, 18, and 21), intracranial anomalies, spinal dysraphism, cleft palate, microphthalmia, tracheoesophageal fistula, and cardiac anomalies [22,81].
●MSAFP levels are highly elevated (if obtained), 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 anomalies. Both fetal and newborn mortality are increased, particularly in fetuses with encephaloceles associated with other anomalies [72]. Preterm birth and fetal growth restriction may occur and increase morbidity and mortality risks. 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 anomaly results from a developmental arrest during the third postmenstrual week in which embryonic cervical retroflexion persists and leads to failure of the neural groove to close in the area of the cervical spine or upper thorax [90-92].
Prenatal diagnosis — The sonographic diagnosis has been made as early as 12.5 to 13 postmenstrual weeks [75,93]. The three major diagnostic features are [90,91,93-97]:
●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 [98].
Associated findings — Associated anomalies occur in up to 84 percent of cases and include [90,94,95,99,100]:
●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 [101].
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) anomalies 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 an open spine with protrusion of the spinal contents through the bony defect. The term myelomeningocele refers to a sac containing the neural placode, cerebrospinal fluid, and meninges that protrudes through a defect of the vertebral arches, extends through the intervening tissue, and bulges beyond the fetal surface (image 7). By comparison, the term myelocele refers to a midline plaque of neural tissue that protrudes through a defect of the vertebral arches and extends through the intervening tissue until it is flush with the fetal surface (image 8). It is not covered by skin or contained by a sac and does not bulge. Myelomeningocele and myelocele are usually associated with hydrocephalus. Three-dimensional ultrasound examination may aid in diagnosis. Chromosomal microarray should be offered given the high risk of aneuploidy. (See 'Spinal dysraphism' above.)
●Anencephaly – Anencephaly is a lethal abnormality in which the cranium as well as 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 the skull is absent above the orbits anteriorly and above the cervical spine posteriorly. Interruption of the pregnancy is an option 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) or rarely 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.)
