Cerebellar volume as measured by MRI increased at a constant rate from birth to term-equivalent age. However, in premature newborns with IVH, cerebellar growth was impaired. No association was found with WMI, suggesting novel mechanisms including the effects of blood products in the CSF and meningeal effects on cerebellar parenchymal development. Cerebellar volume increased at a constant rate after adjusting for brain injury, including IVH, WMI, and cerebellar hemorrhage. Of note, these results should only be used for prediction of cerebellar volumes during the preterm period, as this linear relationship may not continue later in development. These normative data are comparable with those previously reported at term equivalent age.[4
] In addition, these results compare favorably to those reported for fetuses at the same gestational ages determined by ultrasound and MRI, suggesting that cerebellar growth in preterm newborns without significant supratentorial injury is similar to growth in utero
Severity of IVH was inversely associated with cerebellar volumes, but WMI was not associated with any adverse effect on growth. These findings contrast with previous studies, which found decreased cerebellar volumes associated with both severe IVH and WMI.[9
] In contrast with previous reports where MRIs were analyzed at term-equivalent age or later in life, this study analyzed serial MRIs during the preterm period. The results in this study also are in concordance with a previous study of cerebellar diffusion tensor imaging in preterm neonates, where changes in mean diffusivity and fractional anisotropy were associated with IVH but not WMI during the early preterm period.[11
] Taken together, these results suggest differential mechanisms for effects on brain microstructural maturation and cerebellar growth patterns associated with IVH and WMI.
This study highlights that cerebellar volume changes can be appreciated much earlier than previously reported for term equivalent brains. One explanation for these early changes may be that of concurrent injury to the cerebellum during the onset of IVH in the preterm period. Another explanation may invoke the toxicity of blood breakdown products such as heme or iron in the cerebrospinal fluid (CSF) as a result of supratentorial hemorrhage. Prior case series have associated superficial siderosis after subarachnoid hemorrhage with cerebellar atrophy or malformation.[20
] In rodent models, the neurotoxicity of blood products, including heme and free iron, wasreported after intraparenchymal or subarachnoid hemorrhage.[23
] The absence of visible blood products in the basilar and pericerebellar cisterns on MRI in our study likely results from the size of the bleeds and the length of the interval between the hemorrhage and the time of imaging.
Because the germinal matrices of the cerebellum lie in the external granular layer (in close proximity to the subarachnoid space) and in the walls of the fourth ventricle, blood deposition in either location may affect generation of new cells and thereby slow the growth of the cerebellum or result in neuronal cell death. The external granular layer continues to be an active germinal zone through the first postnatal year.[26
] Blood in the posterior fossa cisterns could affect cerebellar growth either by direct effects on these germinal matrices or on the surrounding mesenchyme.
The surrounding mesenchyme contributes to the development of the cerebellum. Early studies in newborn hamsters showed that destruction of the meningeal cells resulted in disruption of lamination of the cerebellar cortex and decreased cerebellar volumes, supporting the influence of the leptomeninges on cerebellar growth.[27
] A knock-out of the Foxc1
gene, expressed only in the surrounding mesenchyme and not within the cerebellum, results in hypoplastic malformations in the cerebellum and anomalies of the surrounding cisterns in mice.[28
] Cerebellar hemisphere volume reduction was equally associated with both ipsilateral and contralateral supratentorial IVH. This supports the possibility that blood in the CSF after IVH may be mediating the signals that result in decreased cerebellar volumes during the preterm period. Because CSF mixes in the third and fourth ventricles, exposing both cerebellar hemispheres to equivalent amounts of blood from each cerebral ventricle, it follows that both cerebellar hemispheres would come in contact with any blood in the CSF.
Because previous studies reported contralateral associations between severe IVH and decreased cerebellar volumes, we investigated whether or not subjects with bilateral severe IVH skewed the data. By performing a subgroup analysis excluding patients with bilateral severe IVH, associations were still not found to be contralateral. Excluding patients with bilateral severe IVH, cerebellar hemispheric volumes continued to be significantly associated with the severity of both ipsilateral and contralateral IVH.
Decreased contralateral cerebellar hemispheric volume was found to be associated with severe supratentorial parenchymal brain injury, resulting in contralateral associations that suggest diaschisis as a mechanism of volume loss.[10
] In the current study examining cerebellar growth, bilateral impaired cerebellar growth was found in both mild and severe IVH, with more severe impairment seen with increasing severity of IVH. This supports three different mechanisms for impaired cerebellar growth with IVH – diaschisis after significant supratentorial parenchymal brain injury, bilateral cerebellar injury as a result of concurrent injury, or circulating blood products in the CSF. In addition, the finding of cerebellar involvement even in the face of mild IVH without significant supratentorial parenchymal involvement lends support to the hypothesis that blood products in the CSF impair cerebellar growth.
In contrast to IVH, WMI was not found to be associated with cerebellar volume changes in the early preterm period. As the postulated mechanisms of reduced cerebellar growth after IVH include both the effect of blood products in the CSF and diaschisis from supratentorial parenchymal brain injury, it is necessary to postulate a reason for the lack of association of cerebellar volume loss with WMI. One possible reason is milder WMI in our cohort compared with those previously reported[19
]. Our scoring system is based upon detection of small, focal areas of mild T1 hyperintensity in the cerebral white matter on early postnatal MRI studies. These lesions are more difficult to detect on term-equivalent studies. Other studies at term have thus based the diagnosis of WMI on signal abnormalities as well as cerebral volume loss, which likely represent more severe injury. Thus, the milder degree of WMI in this cohort may explain the different findings regarding WMI and cerebellar growth compared with previous reports. This difference, however, has allowed better appreciation of the effects of IVH upon cerebellar growth.
Although our results highlight associations with IVH, further MRI studies on healthy term babies will help to determine if preterm birth itself affects cerebellar growth. In addition, long-term neurodevelopmental follow-up of these subjects is underway, which will help decide the clinical implications of impaired cerebellar growth.
By comparing the effects of IVH and WMI, this study demonstrates novel associations between supratentorial IVH without parenchymal injury and decreased cerebellar volumes. These novel mechanisms for impairment of cerebellar growth associated with supratentorial brain injury, including the effects of blood products in the CSF on the developing cerebellum and meninges that may secondarily affect cerebellar parenchymal development, highlight previously unknown risk factors and potential targets for future therapies.