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Specialized Diagnostic Studies for Assessment of the Fetal Central Nervous System
INTRODUCTION
Evaluation of the fetal brain is, for obvious reasons, heavily dependent on specialized imaging techniques that have entered the clinical domain over the past five decades. Since its entry into the clinical domain in the late 1960s and early 1970s, obstetrical ultrasound (US) has secured its status as the first-line screening and diagnostic technique for evaluating the fetal brain. Almost three decades later, “modern” fetal magnetic resonance imaging (MRI) arrived in the clinical arena with the availability of ultrafast T2 imaging, which helped overcome significant previous challenges posed by the moving fetus in the intrauterine environment. Ongoing technical advances in both US and MRI, especially in recent years, have allowed for detailed multimodal evaluation of the fetal brain and its placental and cardiovascular support. Fetal brain imaging has become increasingly quantitative, and a broad array of structural, microstructural, metabolic, and brain connectivity measures are now available in many larger fetal centers. From the perspective of the neurologist consulting on cases in which there are fetal central nervous system (CNS) concerns, the usual referral pathway is one in which an obstetrician or maternal-fetal medicine specialist has identified concerns around fetal brain growth and development on prenatal US and has referred the maternal-fetal dyad for specialized neurological evaluation. The latter usually includes a more focused fetal brain US study and, in the majority of cases, evaluation by fetal brain MRI. Especially in cases where there are concerns regarding abnormalities in other organ systems in addition to the brain, the role of genetic mechanisms should be considered as a potential unifying cause. There have been major advances in understanding of the genetic underpinnings of disease in both the genomic and more recently epigenetic domains. The development of noninvasive genetic tests for aneuploidies (and more recently other conditions) through the so-called liquid biopsy examination of cell-free fetal DNA in maternal blood has significantly impacted the practice of genetic screening, but with recognized caveats. Together these developments highlight the need for the clinician to have an understanding of contemporary fetal imaging and neurogenetics to develop a diagnostic plan and formulate a prognosis. Other techniques for evaluating the fetal condition, such as the biophysical profile , are usually performed by obstetricians and maternal-fetal medicine specialists and are reviewed elsewhere ( Chapter 21 ). In the sections that follow, an overview of these different fetal imaging and genetic diagnostic techniques will be given, outlining their strengths, weaknesses, and indications.
IMAGING THE FETAL BRAIN
This section provides an overview of the established and emerging imaging techniques, specific to US and MRI, that have (or are likely to) become the diagnostic standard for evaluation of the fetal CNS.
Ultrasound-Based Imaging of the Fetal Central Nervous System
In the hands of an experienced examiner, US is a sensitive screening and diagnostic modality for evaluation of most fetal brain and spine anomalies. As an initial imaging screening modality, fetal US is often the only imaging test required for assessment. Early US scanning in the first trimester (when MRI is not useful) may identify the most severe CNS anomalies, such as anencephaly and encephaloceles. By 14 weeks’ gestation, a majority of cranial and spinal structures can be identified. Standard planes for fetal brain US include axial images of the ventricles, cavum septum pellucidum, and cerebellum and should identify up to 95% of sonographically detectable CNS anomalies ( Fig. 9.1 ).
Fetal Ultrasound Assessment of Brain Growth and Development
Accurate assessment of cranial growth and maturation is important in the assessment of the fetal brain. Measurements of the fetal biparietal diameter (BPD), head circumference (HC), and transcerebellar diameter are relatively easy to obtain and reproducible ( Figs. 9.2 and 9.3 ) and can be referenced to large normative databases across gestation. Obviously, an accurate assessment of fetal gestational age (GA) is essential, as the clinical approach based on the last menstrual period is often unreliable. First trimester US provides the most accurate GA assessment. A combination of measurements is superior to a single measurement, and software programs provide instantaneous calculation of fetal GA, expected fetal weight estimates, and growth curves. The fetal BPD is the transverse diameter from the external surface of one parietal bone to the inner surface of the contralateral parietal bone at the level of the thalamic nuclei and cavum septum pellucidum ( Fig. 9.2 ). The cephalic index, which measures the relationship between the short and long axes of the fetal head, should be measured if the head shape appears abnormal. The fetal head circumference is obtained from the same axial image used for the BPD ( Fig. 9.2 ). This measurement is more accurate than the BPD in the third trimester as it is less affected by shape. Measurement of the transcerebellar width is also useful in the assessment of brain growth. If an intracranial abnormality is suspected, additional views in the coronal and sagittal plane can help further assess the corpus callosum and cerebellum. Good-quality midline sagittal US images may be difficult to obtain in a moving fetus but provide important information about the integrity of the corpus callosum ( Fig. 9.4 ); such information may be further enhanced by color Doppler demonstration of the normal branching of the pericallosal artery from the anterior cerebral artery and its path along the superior surface of the corpus callosum ( Fig. 9.4B ). Compare Fig. 9.4 with Fig. 2.22 showing abnormal midline vascular arrangement in absence of the corpus callosum. Transvaginal imaging can further improve resolution of the intracranial anatomy.
Three-dimensional (3D) US imaging allows for biplane evaluation of the corpus callosum, cerebellum, and spine, whereas surface rendering provides detailed images of the of the fetal skull, cranial sutures, and face ( Figs. 9.5 and 9.6 ). The capability to evaluate facial features in the fetus is especially useful in cases with brain malformations known to be associated with craniofacial malformations, such as holoprosencephaly ( Fig. 9.7 ; Chapter 2 ). Color Doppler can aid in the evaluation of vascular anomalies, such as vein of Galen aneurysmal malformation (VGAM) ( Fig. 9.8 ; Chapter 41 ).
Fetal growth restriction (FGR), especially the early-onset form ( Chapter 10 ), is an important cause of acquired fetal head growth failure or microcephaly. The ability of US to identify microcephaly or fetal growth retardation is variable and most successful when the disease state is severe. A slowing of the rate of head and femur growth may be apparent with severe FGR but is more difficult to identify when the disturbance is mild or early. Assessing fetal condition using the biophysical profile score or Doppler velocity ratios of the umbilical artery (UA) and/or fetal middle cerebral artery (MCA) are additional useful adjuncts in the diagnosis of FGR ( Chapter 20 ). A comprehensive sonographic review includes not only a survey of the fetus but also evaluation of amniotic fluid volume, cord structure, and placenta. A functional review of the fetus, including hand clenching and swallowing, is also important.
Doppler Assessment of Blood Flow Velocities in the Umbilical and Fetal Vasculature
Although US can provide useful information regarding fetal brain and spine anatomy, its ability to assess fetal health is of tremendous importance as well, particularly in the third trimester. Fetal asphyxia is a spectrum of conditions ranging from transient episodes of hypoxemia to sustained hypoxemia with resultant metabolic acidosis. When asphyxia develops, the fetus redistributes cardiac output from nonvital organs (lung, kidney, skeleton) to vital organs (brain, adrenals, and myocardium) ( Chapter 16 ). This protective redistribution is reflexive, resulting from hypoxemic or acidemic stimulation of carotid chemoreceptors. When sustained, redistribution can be profound. Cerebral asphyxia results in alterations in biophysical activities and responses. Fetal breathing may disappear early, whereas fetal movements disappear only with more severe disease.
Thus flow waveforms from maternal vessels, placental circulation, and fetal systemic vessels provide important information from 12 through 40 weeks’ gestation. Doppler waveforms of the MCA are obtained at the level of the circle of Willis with a high degree of reproducibility ( Fig. 9.9 ). GA-related reference values are available for the UA and fetal vessels, including the MCA. Peak systolic velocities require angle correction. Several ratios that are independent of the angle of insonation can be used for measurement of flow impedance ( Fig. 9.9 ). These ratios include the difference between peak systolic and diastolic flow velocity over the mean flow velocity (pulsatility index), the difference between peak systolic and diastolic flow over the peak systolic flow (resistive index), and the ratio of the peak systolic to diastolic flow, or S/D ratio.
Normally, MCA impedance decreases with advanced GA but remains higher than the UA. Fetal brain sparing during hypoxia is characterized by an increase in diastolic and mean blood flow velocity in the MCA. If vasodilation of the MCA is lost, the fetus will begin to enter the acidotic stage. At term, because evidence of fetal hemodynamic redistribution may exist in the presence of normal UA indices, such ratios as the MCA/UA ratio (cerebroplacental ratio) are useful. Normal cerebral to placental resistance ratio is typically greater than 1.
Ultrasound Findings in Abnormal Fetal Brain Development
Ventriculomegaly ( Chapter 3 )
Enlargement of the lateral ventricles is the most common cranial anomaly detected by fetal US, with an incidence between 0.1% and 1%. Ventriculomegaly is defined as an enlargement of the lateral ventricles with a transverse atrial diameter of 10 mm or larger, typically with separation of the choroid from the medial ventricular wall (“dangling choroid”) ( Chapter 3 ; Fig. 3.5 ). Classification of ventriculomegaly ( Chapter 3 ) is based on its symmetry/asymmetry, ventricular size, or whether it is isolated or associated with other congenital anomalies. Ventricular size, specifically of the lateral ventricle trigone, is measured by fetal US in the axial plane at the level of the thalami, just posterior to the glomus of the choroid plexus. Different classifications of ventriculomegaly have been proposed, the most common being mild (between 10 and ≤12 mm), moderate (>12 and ≤15), and severe (>15 mm) ventriculomegaly. In the fetus with ventriculomegaly the incidence of associated brain and somatic anomalies increases with ventricular size.
Microcephaly
The diagnosis of microcephaly is made with reference to normative population-based nomograms, although the precise cut-off varies between studies. A head circumference more than two standard deviations below the established mean value for GA has been widely used as diagnosis of microcephaly; however, more recent reports have described generally favorable neurodevelopmental outcomes in fetuses with isolated HC measures between two and three standard deviations below the mean. A fall-off in head growth may be delayed until the third trimester or later. FGR (especially early onset) due to placental failure ( Chapter 10 ) may be a cause of microcephaly, and this etiology should be considered based on other fetal growth measurements (e.g., abdominal circumference, long bone length) and on Doppler US flow velocities in the uterine, umbilical, and cerebral arteries ( Chapter 10 ). Features such as intracranial calcifications and mineralizing vasculopathy may point to an infectious cause for microcephaly. Although microcephaly may appear isolated, more than 80% of cases have additional anomalies, including cortical malformations, which are difficult to visualize by US, especially in the fetus.
Holoprosencephaly ( Chapter 2 )
Holoprosencephaly is defined as absent or incomplete embryonal brain segmentation with resultant abnormal midline union of the telencephalon +/− diencephalon. Classical holoprosencephaly occurs along a disease spectrum from alobar (most severe) to semilobar (intermediate) to lobar (least severe) subtypes. Alobar holoprosencephaly ( Fig. 9.7 ) is easily diagnosed by fetal US and is readily distinguished from other subtypes on US by the findings of delayed/malformed cerebrum with absent midline structures (septum pellucidum, corpus callosum, and falx cerebri). A single, large, horseshoe-shaped ventricle with a choroid plexus that runs transversely is an imaging hallmark. The basal ganglia and thalami are fused, and the cerebrum forms a “pancake-like” structure around the monoventricle. Facial deformities (clefting, cyclopia, hypotelorism) may be severe. Semilobar and lobar holoprosencephaly and middle interhemispheric variant/syntelencephaly forms of holoprosencephaly are more difficult to identify by US.
Corpus Callosum Anomalies ( Chapter 2 )
When the developing corpus callosum is short and thin early in gestation, the presence or absence of the septum pellucidum and size and shape of the ventricles are the most useful US markers of a corpus callosum abnormality. Good-quality US images in the sagittal midline may be difficult to obtain ( Fig. 9.4A ), and coronal and axial planes assessing the cavum septum pellucidum are important ( Fig. 9.1 ). US findings in complete agenesis of the corpus callosum (ACC) include ventriculomegaly (of the posterior horns, colpocephaly), parallel orientation of the lateral ventricles, absent septum pellucidum, upward displacement of the third ventricle, and a deep interhemispheric fissure that extends to the third ventricle roof. On coronal images the third ventricle may extend superiorly into an interhemispheric cyst ( Fig. 9.10 ). With callosal agenesis the pericallosal artery ( Fig. 9.4B ) may assume a more vertical orientation by color Doppler ( Fig. 2.22 ). If a lipoma is present, a midline echogenic mass may be noted.
Septo-optic Dysplasia ( Chapter 2 )
Septo-optic dysplasia is usually a sporadic condition characterized by hypoplasia of optic nerves and chiasm, absent/abnormal septum pellucidum, and underdeveloped hypothalamic structures with postnatal endocrine disturbances. Coronal fetal US images reveal moderate ventricular dilatation, absent/hypoplastic septum pellucidum, and box-like frontal horns. Optic nerve evaluation is usually below the resolution of fetal US, and even that of fetal MRI.
Arachnoid Cysts ( Chapter 4 , Chapter 41 )
Congenital arachnoid cysts are believed to be caused by an unexplained splitting of the arachnoid membrane layers and subsequent accumulation of cerebrospinal fluid (CSF) that expands into a cyst. These lesions typically do not communicate with the subarachnoid space. The most frequent locations are the Sylvian fissures. Because US is based on the reflection of sound waves at the interface between tissue types (such as CSF and membranes), it is often superior to MRI in identifying septations and cystic structures, especially small cysts.
Arteriovenous Malformations
Fetal arteriovenous malformations are the result of abnormal differentiation of the connections between the arterial and venous systems. The most common fetal arteriovenous malformation, the VGAM ( Chapter 41 ) ( Fig. 9.8A ), is actually an abnormal arteriovenous communication between the developing choroidal arteries and the median prosencephalic vein of Markowski, which fails to complete normal full regression. On US, the VGAM appears as a hypoechoic mass cephalad to the pineal region, which shows abnormal and low resistive flow patterns by color Doppler ( Fig. 9.8B ).
Neuronal Migration Disorders ( Chapter 6 )
Neuronal migration disorders may result from any insult, including genetic, infectious, inflammatory, ischemic, and toxic insults, during critical periods of neuronal migration. Schizencephaly is a severe neuronal migration disorder that is often missed by prenatal US, although wider, open-lip lesions and associated ventriculomegaly may be demonstrated. Heterotopic gray matter represents neurons arrested in ectopic locations during their migration between the 6th and 24th gestational weeks. They may be found anywhere in the cerebrum or cerebellum between the subependymal regions centrally to the subcortical white matter peripherally, with lateral ventricular subependymal heterotopia the most common. Subependymal heterotopia may be recognized by irregular inner ventricular margins. Small heterotopia and subcortical heterotopias are more difficult to detect by US.
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