Diagnostic imaging tools to elucidate decreased cephalic biometry and fetal microcephaly: a systematic analysis of the central nervous system

Although the most important feature warranting investigation of central nervous system (CNS) disorders during prenatal examination is ventriculomegaly, anomalies of cephalic biometry are also an important clue to the presence of fetal cerebral pathology. In routine practice, any decrease in cephalic biometry to < 5th percentile raises suspicion of underlying microcephaly. However, as discussed below, distinction must be made between suspicion of microcephaly and true microcephaly. True fetal microcephaly (as defined in Tool 2) is associated, in many prenatal cases, with morphological anomalies1–3. It may be considered as part of a complex disorder, such as syndromes with or without chromosomal anomalies, or it may be associated exclusively with cerebral anomalies1,3, being related either to primary cerebral organization disorders affecting all steps of CNS development, or to clastic events due to ischemohemorrhagic or infectious conditions; the latter is of particular interest currently, in light of the recent emergence of microcephaly related to Zika virus infection1–5. Primary cerebral organization disorders include disorders of neural tube development (neural tube defect), prosencephalon cleavage (holoprosencephaly), precursor cell proliferation (microcephaly with simplified gyral pattern), neuroblast migration (lissencephaly) and corticogenesis (polymicrogyria). In all these cases, microcephaly is associated with structural CNS anomalies. However, in some cases, microcephaly can be truly isolated, i.e. with no associated structural anomalies, often being related to familial disorders and transmitted mostly as an autosomal recessive trait1. In such cases, prenatal cephalic biometry is usually within the normal or subnormal limits and microcephaly develops after birth, with dramatic worsening of cephalic biometry during the first years of postnatal life6,7. Such isolated familial microcephaly is rarely of concern when facing isolated microcephaly in the prenatal period. As published previously for ventriculomegaly8, we outline here our systematic approach to the management of patients referred to our institution due to an unexplained decrease in cephalic biometry. Our approach is based on a set of diagnostic tools to diagnose and elucidate a decrease in fetal cephalic biometry, which may lead to suspicion of microcephaly with underlying CNS structural anomalies. It should be noted that its application should always be guided according to the clinical context. These tools are tailored for ultrasound examination, as recommended by Persutte9 and Kurtz et al.10, but can also be used for magnetic resonance imaging (MRI) investigation. Indeed, this etiological approach to the diagnosis of microcephaly is a perfect illustration of the potential contribution of MRI to the investigation of CNS anomalies, as ultrasound is often limited in more severe cases as a result of poor acoustic windows due to the narrowing of the sutures. In such cases, MRI undoubtedly offers more information than does ultrasound for cerebral anatomical analysis, especially regarding complete gyration and pericerebral space examination during the third trimester of pregnancy11. Finally, we should emphasize that this article is intended not as an epidemiological study, but as a proposal to conduct a systematic analysis of the CNS when facing unexplained decreased cephalic biometry, based on a selection of pedagogical cases.