Child Neurology: Cortical Malformations in Preterm Infants

Discussion

We report the imaging findings and neurodevelopmental outcomes of an infant born very preterm with MCD that was detected incidentally on research neonatal brain MRIs. Overall, MCD were detected incidentally in 2 infants from a larger prospective cohort study of 160 children born very preterm enrolled from 2 neonatal intensive care units of 1 city; the other child with incidental findings was lost to follow-up. This case illustrates the neuroimaging evolution of MCD from early life to term-equivalent age. Early brain ultrasounds in preterm infants may be useful in screening for brain injury; however, this report demonstrates the complementary role of brain MRI in detecting brain malformations. Detecting MCD and other brain malformations early allow for appropriate investigations and close neurodevelopmental follow-up.

Very preterm infants are born during a period of rapid brain maturation and growth, when many cortical developmental processes are still occurring. There are 3 main stages of cortical development: neuronal proliferation in the ventricular zone (peak between weeks 9 and 12 of gestation), migration of neurons to the developing cortex (peak between weeks 13 and 18 of gestation), and postmigrational processes including cortical organization and development of neuronal connectivity (begins at approximately 17 weeks of gestation and continues for years postnatally) (Table).^1,–,4 It is important to note that disruptions in early stages of cortical development can affect subsequent stages because many cortical developmental processes occur simultaneously. Different brain regions also undergo cortical development at different periods.^2,5 Furthermore, the same genes can regulate processes occurring at different stages of cortical development.^2,5,6 Thus, MCD may present as a combination of multiple cortical malformations and are often associated with other brain malformations.⁵ For example, the reported case presents a combination of MCD with malformations of neuronal migration (periventricular nodular heterotopia) and postmigrational cortical developmental disorders (closed-lip schizencephaly).

Abnormalities in cortical structural development are now increasingly recognized in children born preterm.⁷ In preterm infants, there is an increased potential for disruption of cortical developmental processes during the prenatal, perinatal, and postnatal periods. This increased potential for disruption may be secondary to obstetric complications or neonatal clinical instability, which can result in ischemic brain injury. Of importance, an association between brain malformations, including MCD, and preterm birth has been reported.⁸ Thus, although rare, MCD are an important differential to consider in preterm infants with atypical neurodevelopmental trajectories, focal neurologic abnormalities, or focal seizures.

With recent advances in neuroimaging, MCD can be detected antenatally with ultrasound or MRI.^9,10 However, for the patient described, antenatal ultrasound performed as part of routine antenatal care in the early second trimester was normal. An early postnatal clinical head ultrasound, performed as part of routine neonatal screening in Canada to detect preterm brain injury (intraventricular hemorrhage and periventricular leukomalacia),¹¹ in this infant revealed early ischemic changes. Subsequently, MCD were detected on the child’s research MRI, after which he was referred to clinical genetics and neurology for further investigations and management. Head ultrasound can also be useful in looking for signs of brain malformations or associated features such as the presence of calcifications or ventriculomegaly.¹² However, brain changes in MCD can be subtle, and brain MRI offers better characterization of the cortical anomalies along with any associated brain malformations and prematurity-related brain changes that may be missed by ultrasound.^2,13 Thus, the recommended neuroimaging modality for characterizing atypical head ultrasound findings and detecting MCD is brain MRI.

The appearance of MCD may become more conspicuous over time. This neuroimaging evolution of MCD over time was previously demonstrated in a case report of a very preterm infant with minor abnormalities in the perisylvian regions noted on MRI at 31 weeks PMA, followed by extensive bilateral perisylvian polymicrogyria observed on MRI at 3 months corrected age.¹⁴ In that case, an underlying ischemic etiology was suspected, given the simultaneous presence of extensive bilateral cystic periventricular leukomalacia in the infant. Of interest, similar to that case, we report the evolution of imaging findings between brain MRIs performed early in life and at term-equivalent age in our patient, for whom we suspect an ischemic underlying cause. Indeed, our hypothesis is that this preterm neonate experienced an ischemic brain injury, probably during birth, which subsequently altered cortical development. This hypothesis is supported by the early ischemic changes detected on head ultrasound (on day of life 2), the presence of unilateral MCD and evolution on neuroimaging. Detection of MCD can depend on timing of the MRI because the long-lasting consequences of early ischemic injury can evolve over time. In addition, ongoing myelination alters the appearance of the gray-white matter junction.² It is easiest to differentiate cortex from white matter, and MCD, before myelination begins (neonatal period) or after myelination is complete (after 2–3 years of age) because contrast between cortex and white matter decreases during myelination.^2,15 Thus, it may be necessary to repeat neuroimaging studies after completion of myelination in patients with a high suspicion for MCD.

This study reports the neuroimaging findings and neurodevelopmental trajectory of a child born very preterm with MCD detected incidentally on neonatal brain MRIs. The clinical relevance of this case includes the complementary role of brain MRI detecting MCD in a preterm infant with suspicious findings on neonatal head ultrasounds. The neuroimaging evolution over the neonatal period underlines that brain development is dynamic, with ongoing changes in the postnatal period. During this crucial period for brain development, cortical developmental processes may be altered by various mechanisms, including ischemic injury, and result in MCD. Thus, in cases of suspicious head ultrasound findings, neuroimaging with brain MRI is indicated to detect MCD and could be repeated at approximately 2 years of age after myelination is complete to understand the full extent of the MCD. Finally, this case highlights the importance of having a broad differential for brain abnormalities in infants born very preterm, which includes MCD in addition to brain injury.