We found that prenatal isolated MVM is associated with significantly enlarged lateral ventricles on postnatal MRI, indicating enlargement of the lateral ventricles detected in the second trimester persists at least through neonatal brain development. In addition to enlarged lateral ventricles, neonates with prenatal MVM had greater cortical gray matter volumes and evidence of reduced cortical white matter volumes. Finally, quantitative DTI tractography revealed larger MD and radial diffusivity, and reduced FA in developing corpus callosum and cortico-spinal tracts. These findings indicate that prenatal MVM is a marker of altered cortical development in the neonatal period.
Neonatal lateral ventricle volume was highly correlated with prenatal lateral ventricle width, indicating that relative lateral ventricle size is conserved throughout the second half of prenatal brain development into the neonatal period. Even cases in which the lateral ventricle width “normalized” or fell below 1.0 cm width on later ultrasounds had significantly enlarged lateral ventricles compared to controls. In a case series, we have previously found that fetal lateral ventricle enlargement can persist until ages 6–9 years in some cases (6). Therefore, it appears that prenatal lateral ventricle structure is conserved well into childhood and may serve as a prenatal marker of altered childhood brain development. Bloom et al. (27) found a significant linear relationship between prenatal ventricle width and decreased mental development index of the Bayley Scales of Infant Development at a mean age of 21 months, evidence that prenatal ventricle structure can be predictive of postnatal neurocognitive development.
Interestingly, prenatal isolated MVM was associated with greater cortical gray matter volume in the neonatal period and larger lateral ventricle volume was associated with larger cortical gray matter volumes in both the control and MVM groups. Cortical neurogenesis occurs in the ventricular and subventricular zones of the developing human brain (39, 40
), and it has been proposed that the evolutionary enlargement of the cortex in humans is related in part to expanded lateral ventricle size and increased numbers of neuronal progenitor cells (41). It is possible that a larger lateral ventricle would have a greater volume of ventricular and subventricular zone proliferating cells associated with it, giving rise to more gray matter, as the lateral ventricle enlargement observed in MVM is present before many of the neurons of the cortex are formed (42). Because the skull is developing and not closed during this period, any enlargement of the lateral ventricle and cortical gray matter would be accommodated by an enlarging skull. There was no difference in cerebellum volume between groups, indicating that enlargement in the MVM cases was not generalized throughout the brain. There is also evidence that the flow of cerebrospinal fluid within the lateral ventricle influences migration of neuroblasts to the olfactory bulb in mice (43). An abnormally enlarged lateral ventricle could potentially have abnormal CSF flow altering migration of neurons and cortical development.
Autism has been associated with increased cortical gray and white matter volumes; this increased growth appears to occur in the first year or two of life (44, 45
). Increased lateral ventricle volumes have been observed in autism (3), and it is temping to speculate that enlarged lateral ventricles could possibly give rise to enlarged gray matter volumes in some forms of autism. There is enormous growth of gray matter, and a less robust growth of white matter in the first two years of life in normal children (46); it will be important to determine if increased lateral ventricle size is associated with increased cortical gray matter development in the first two years of life. We are obtaining follow-up MRIs at ages one and two years in this cohort and hope to address this question. Other disorders of neurodevelopment have been also associated with increased regional or global cortical gray matter volumes, including neurofibromatosis (47), prematurity (48), ADHD (49–51
) and cleft lip/palate (52).
There was a difference in the correlations between lateral ventricle volume and cortical white matter volume in the MVM and control groups, to the extent the correlation in controls reflects normal development, this difference suggests MVM cases have altered cortical white matter development. In general, mean diffusivity decreases with age and fractional anisotropy increases with age in the neonatal period (37, 53
), presumably reflecting increasing organization and myelination of white matter tracts. Radial diffusivity decreases with increasing myelin development in the rodent corpus callosum(55). In the human neonatal period, MD appears to be more sensitive to changes in myelination than FA (37). The overall smaller white matter volume, along with greater MD, greater radial diffusivity, and smaller FA observed in infants with MVM suggests either that there is a temporal lag in white matter development, or that white matter is abnormal. Longer-term follow-up studies will need to be done to differentiate these possibilities.
The definition of mild ventriculomegaly has been debated in the literature (56, 57
). An atrial width of 1.0 cm on prenatal ultrasound is 3–4 standard deviations from the mean 20
. Outcome studies indicate that atrial widths of 1.2 cm or greater are more often associated with an unfavorable outcome than widths of 1.0–1.2 cm (24–26
), and it has been argued that widths between 1.0 and 1.2 cm should be considered normal (58). The mean maxiumum lateral ventricle width for our MVM cases was 1.15 cm, placing them in the lower range of MVM. It is important to note that prenatal atrial widths in the 1.0–1.2 cm range in this study are associated with significant enlargement of the lateral ventricle in the neonatal period (), as well as alterations of cortical gray and white matter.
In our sample, boys were more likely to have MVM than girls, with a gender ratio of 3.25. This male bias is consistent with previous studies of MVM, with gender ratios ranging from 1.3 to 3.0 (6, 19
). There is evidence that males have larger prenatal atrial widths than girls (13, 59
) though we did not find gender differences in lateral ventricle volume on neonatal MRI (46). The predominance of males with MVM is consistent with higher rates of many neurodevelopmental disorders in males, and provides evidence that males are more vulnerable to alterations of brain development.
Ultimately, the value of lateral ventricle enlargement as a prenatal or neonatal structural marker of risk will need to be determined in long-term outcome studies. Most outcome studies of MVM are limited to the first few years of childhood, have not followed the children into the age of risk and involve interviews of parents and review of clinical records. Only Bloom et al. (27) has conducted a prospective, standardized follow-up study and found that a third of children had evidence of developmental delays. In a case series we previously found that MVM can be associated with autism, attention deficit-hyperactivity disorder, and learning disabilities (6), suggesting that prenatal MVM may be a marker of risk for these disorders. We are obtaining follow-up MRIs and neurodevelopmental assessments on this cohort and hope to follow these children into later childhood. A present, prenatal MVM is, at best, a non-specific marker of risk for a variety of poor neurodevelopmental and neuropsychiatric outcomes. In addition, it should be noted that there is overlap between the MVM subjects and controls in cortical gray and white matter and lateral ventricle volumes, making the predictive value less certain. Future studies may provide the basis for more specificity.
In summary, mild enlargement of the lateral ventricles in the fetal brain is associated with enlarged lateral ventricles after birth, as well as evidence of altered cortical gray and white matter development. The overall relative size of the fetal lateral ventricle appears to be conserved into the early postnatal periods and beyond, suggesting that it may have value as an early structural marker of risk for poor neurodevelopmental outcome and neuropsychiatric disorders associated with enlarged lateral ventricles. The study of prenatal and neonatal brain development with ultrasound offers the potential for an improved understanding of neurodevelopmental mechanisms that contribute to neuropsychiatric disorders as well as very early identification of children at risk.