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Review
. 2009 Sep;24(9):1085-104.
doi: 10.1177/0883073809338067.

Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important

Joseph J Volpe  1
Affiliations
Review

Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important

Joseph J Volpe. J Child Neurol. 2009 Sep.

Abstract

Brain abnormality in surviving premature infants is associated with an enormous amount of neurodevelopmental disability, manifested principally by cognitive, behavioral, attentional, and socialization deficits, most commonly with only relatively modest motor deficits. The most recognized contributing neuropathology is cerebral white matter injury. The thesis of this review is that acquired cerebellar abnormality is a relatively less recognized but likely important cause of neurodevelopmental disability in small premature infants. The cerebellar disease may be primarily destructive (eg, hemorrhage, infarction) or primarily underdevelopment. The latter appears to be especially common and relates to a particular vulnerability of the cerebellum of the small premature infant. Central to this vulnerability are the extraordinarily rapid and complex developmental events occurring in the cerebellum. The disturbance of development can be caused either by direct adverse effects on the cerebellum, especially the distinctive transient external granular layer, or by indirect remote trans-synaptic effects. This review describes the fascinating details of cerebellar development, with an emphasis on events in the premature period, the major types of cerebellar abnormality acquired during the premature period, their likely mechanisms of occurrence, and new insights into the relation of cerebellar disease in early life to subsequent cognitive/behavioral/attentional/socialization deficits.

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Conflict of interest statement

The authors have no conflicts of interest to disclose with regard to this article.

Figures

Figure 1
Figure 1
Cerebellar volume as a function of gestational age. The three curves are the 5th, 50th, and 95th percentile values of cerebellar volume obtained by 3-dimensional volumetric ultrasonography. Data obtained from 231 studies of fetuses from 20 to 40 weeks’ gestation and expressed as percentage of cerebellar volume at 40 weeks’ gestation. The 100% value is the 50th percentile value at 40 weeks’ gestation (absolute value, 17.6 mL). Note the dramatic increase in cerebellar volume from 24 to 40 weeks’ gestation. SOURCE: Adapted from Ultrasound Med Biol. 2000;26(6):981–988.
Figure 2
Figure 2
Growth of the cerebellar surface from 24 to 40 weeks. Drawings were made in the mid-sagittal plane. Note the extraordinary increase from 24 weeks to 40 weeks in cerebellar surface area, related primarily to increased foliation but also to increased overall cerebellar growth. SOURCE: Adapted from J Comp Neurol. 1970;139(4):473–500.
Figure 3
Figure 3
Two proliferative zones in cerebellar development. Transverse section of the rhombencephalon at approximately 14 weeks’ gestation. Note the dorsally placed ventricular zone (VZ, blue) and the dorsolaterally placed rhombic lip (RL, red). Arrows indicate directions of migration. The VZ gives rise to interneurons of the deep nuclei, for example dentate (De), and to the Purkinje cells. The RL has 2 portions divided by the choroid plexus (cpl) of the fourth ventricle (4V); the upper portion gives rise to granule precursor cells of the external granular layer (EGL) and to projection neurons of the deep nuclei, and the lower portion gives rise to neurons of the basis pontis and inferior olive (OL). SOURCE: Adapted from Brain Res. 1973;62(1):1–35.
Figure 4
Figure 4
Major events in the histogenesis of the cerebellum in 4 major time periods from 9 weeks of gestation to 7 months postnatal (pn). The 2 zones of proliferation are the ventricular zone (VZ) and the external granule cell layer (EGL). Three directions of migration are indicated by arrows, that is radial from the VZ, tangential over the surface of the cerebellum to form the EGL, and later, inward to form the internal granular layer (IGL). Proliferation in the outer half of the EGL is under positive control by Sonic hedgehog (Shh) secreted by Purkinje cells (P-cells). Note the markedly active proliferation and migration of the granule precursor cells of the EGL during the premature period. Not shown is the marked increase in size of the molecular layer (ML) during the postnatal period. De, dentate; IZ, intermediate zone; pn, postnatal; WM, white matter. SOURCE: Adapted from J Comp Neurol. 1970;139(4):473–500; Brain Res. 1973;62(1):1–35; and J Neurol. 2003;250(9):1025–1036.
Figure 5
Figure 5
Cerebellar underdevelopment as evidenced by magnetic resonance imaging at 7 months of age in an infant born at 29 gestational weeks. Sagittal image (A) shows markedly small vermis and pons below the inclined tentorium. Coronal image (B) shows small cerebellar hemispheres immediately below the tentorium. SOURCE: Reproduced with permission from AJNR Am J Neuroradiol. 2005;26(7):1659–1667.
Figure 6
Figure 6
Cerebellar underdevelopment and hemosiderin deposition by magnetic resonance imaging (MRI) in a newborn at term equivalent age. Sagittal T2-weighted MRI (A) from a 13-week-old infant born at 26 weeks’ gestation shows small vermis, enlarged fourth ventricle, reduced dimensions of the brain stem, and inclined tentorium; hemosiderin deposition is apparent on the surface of the pons and the lining of the fourth ventricle (black arrows). Horizontal MRI (B) shows reduced volume of cerebellar hemispheres with hemosiderin deposition in both hemispheres (black arrows). SOURCE: Reproduced with permission from Eur J Paediatr Neurol. 2008;12(6):455–460.
Figure 7
Figure 7
Likely mechanisms by which direct adverse effects on the external granule cell layer lead to diminished volumetric development of cerebellum and pontine and olivary nuclei. See text for details.
Figure 8
Figure 8
Glucocorticoid (GC) receptor immunoreactivity in the external granular layer (EGL) of the developing cerebellum. Glucocorticoid receptor immunohistochemistry in the postnatal day 7 mouse pup shows specific, dramatically elevated levels of immunoreactivity in the EGL. At this specific time point, a single GC injection in vivo leads to marked degeneration. IGL, internal granular layer; ML, molecular layer; PCL, Purkinje cell layer; WM, white matter. SOURCE: Reproduced with permission from Cell Death Differ. 2008;15(10):1582–1592.
Figure 9
Figure 9
Major afferent and efferent connections between cerebrum and cerebellum. In premature infants, the most likely disturbances of afferent connections occur at the level of the cerebrum (cerebral white matter and cortex) and of efferent connections at the levels of the cerebellum and thalamus. See text for details.
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