Chapter 5: Cerebellar hemorrhage in the preterm newborn

Jarred Garfinkle, Emily W.Y. Tam

Chapter outline

Key Points
Case History
Introduction
Cerebellar Development, Organization, Functional Topography, and Injury
Preterm Cerebellar Hemorrhage
Outcomes Following Preterm Cerebellar Hemorrhage
Returning to the Case
Conclusions
References

Key points

• Cerebellar hemorrhages (CBH) likely originate from the external granular layer, which is a superficial germinal matrix within the immature cerebellum.
• The anterior lobe of the cerebellum is principally connected with sensorimotor cortex, while the posterior lobe is connected with association regions of the cerebral cortex.
• Cranial ultrasound is only capable of detecting relatively large CBH, while MRI can detect punctate CBH, which are typically classified as those less than 4 mm in diameter.
• CBH has been associated with motor, visuomotor, cognitive, and behavioral problems in early childhood.
• Larger CBH and those affecting the vermis and deeper aspects of the cerebellar hemispheres are more likely to be associated with neurodevelopmental deficits than superficial punctate CBH.

Case history

AM was a 600 g 24-week male neonate born to a 30-year-old mother after preterm labor. The mother received two doses of betamethasone but not magnesium sulfate. He was delivered vaginally and his umbilical cord was quickly clamped. At birth he demonstrated minimal respiratory effort and was intubated in the delivery room with a subsequent rise in heart rate. He was subsequently given surfactant for respiratory distress syndrome. On day of life 2 he developed hypotension and anemia for which he received a packed red blood cell transfusion and inotropes. His head ultrasound on day of life 3 revealed bilateral intraventricular hemorrhage with left periventricular hemorrhagic infarction and echogenicities within both cerebellar hemispheres. A repeat head ultrasound on day of life 6 with dedicated views via the mastoid fontanel confirmed bilateral cerebellar hemorrhages (CBH) (Fig. 5.1). Subsequent head ultrasounds showed the evolution of the CBH and an MRI at 34 weeks postmenstrual age showed severe cerebellar atrophy in addition to supratentorial pathologies (Fig. 5.2).

Fig. 5.1Ultrasound images over time of the 24-week preterm male depicted in the case study. *Upper left panel:* Coronal image on day of life (DOL) 3 via the anterior fontanel demonstrating bilateral intraventricular hemorrhage within the posterior horns of the lateral ventricles with left periventricular hemorrhagic infarction and bilateral cerebellar hemisphere echogenicities suspicious for hemorrhage (*arrowhead*). *Upper right panel:* Sagittal right image on DOL 3 via the anterior fontanel demonstrating echogenicity within the inferior portion of the cerebellar hemisphere (*arrowhead*). *Bottom left panel:* Ultrasound image on DOL 6 via the left mastoid fontanel demonstrating echogenicities within both cerebellar hemispheres suggestive of cerebellar hemorrhage (*arrowheads*). Ultrasound image on DOL 19 via the left mastoid fontanel demonstrating lesions with echogenic rims in both cerebellar hemispheres, likely representing the subacute phase of the cerebellar hemorrhages (*arrowheads*).

Several questions related to CBH were asked by the bedside staff and the parents: Why did AM develop CBH? Could they have been prevented? How will the CBH impact his life?

Introduction

Cerebellar hemorrhage (CBH) is a category of preterm brain injury and typically affects newborns born at the lowest gestational ages.¹^,² Similar to the supratentorial intraventricular hemorrhages, CBH likely originate from the germinal matrices of the immature cerebellum, and in particular the external granular layer (EGL) which is superficially located beneath the pial layer.^3–5 The original reports of CBH in preterm neonates relied on postmortem examinations.⁶ Subsequently, in the 1980s, reports of CBH detected by ultrasound (US) via the anterior fontanel were described, including by the editor of this textbook.⁷ In the 1990s cranial US via the mastoid fontanel provided greater details of CBH.² These large hemorrhages described before the more widespread use of MRI in neonatology were associated with death and severe neurodevelopmental impairments.²^,⁸

More recently, large CBH have become less common with improvements in the care of the preterm newborn. However, with the increasing use of MRI, smaller CBH referred to as punctate CBH have been increasingly reported in the preterm population.⁹^–¹³ These punctate CBH are typically defined as those only visible on MRI and measuring <4 mm in diameter on any given imaging plane.¹⁴^,¹⁵ Two recent systematic reviews found wide variations in reported outcomes of preterm children with CBH, likely due to the heterogeneity of the hemorrhages themselves.¹⁶^,¹⁷ Thus it is important to assess the size and location of the CBH and understand the functional topography of the cerebellum.

This chapter reviews the development and function of the cerebellum and the diagnosis and implications of CBH in preterm newborns.

Cerebellar development, organization, functional topography, and injury

In order to understand the impact of CBH on neurodevelopment, an understanding of the developmental processes that occur in the immature cerebellum and its ultimate anatomic and functional organization is essential. The cerebellum is vulnerable during the preterm period because the cerebellum is in a state of rapid development in the third trimester.³ During the third trimester, cerebellar volume increases fivefold and the cerebellar surface area increases 20-fold.³^,¹⁸ Cerebellar proliferation continues into the second postnatal year, by which point the cerebellum contains the majority of all neurons in the central nervous system.¹⁹ The cerebellar cortex is folded into multiple lobes and lobules to accommodate such a large number of cells.

Cerebellar development and vasculogenesis

There are two primary neuronal progenitor zones in the developing cerebellum: the rhombic lip, which forms in the dorsolateral part of the alar plate adjacent to the fourth ventricle, and the ventricular zone, which forms on the ventral surface of the alar plate along the lining of the fourth ventricle.⁴^,²⁰^,²¹ Progenitor cells from the rhombic lip migrate outward to beneath the pial membrane, to form the EGL.²² The EGL, therefore constitutes a secondary germinal zone, or transit amplifying center, as it still contains progenitor cells. Neurogenesis in the ventricular zone peaks in the first trimester, whereas neurogenesis in the EGL appears at the end of the embryonic period and persists for several months to 2 years after birth (Fig. 5.3). The Purkinje cells, GABAergic projection neurons, and later the Golgi, stellate and basket interneurons and Bergmann glia arise from the ventricular zone whereas the granule cells, glutaminergic projection neurons, and unipolar brush cells arise from the EGL.²³

Fig. 5.3Major events in the histogenesis of the cerebellum in four major time periods from 9 weeks of gestation to 7 months postnatal (pn). The two 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 Rakic P, Sidman RL. Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans. *J Comp Neurol.* 1970;139(4):473–500; Sidman RL, Rakic P. Neuronal migration, with special reference to developing human brain: a review. *Brain Res.* 1973;62(1):1–35; and ten-Donkelaar HJ, Lammens M, Wesseling P, Thijssen HOM, Renier WO. Development and developmental disorders of the human cerebellum. *J Neurol.* 2003;250(9):1025–1036.)

The EGL comprises two sublayers: an external proliferating zone and an inner differentiating zone, which are separated by a vascular bed.⁴^,²¹ Neuronal precursor proliferation peaks in magnitude during the third trimester in the EGL, induced by sonic hedgehog (SHH) protein secreted by differentiating Purkinje cells.²⁴ As a result, the EGL and its vascular bed are susceptible to myriad insults during the preterm period. Peak EGL proliferation occurs around postnatal day 7 in mice, which approximately corresponds to the first half of the third trimester in humans. The progenitor pool of the EGL persists longest in the posterior lobe.²¹ As precursor neurons mature, they exit the EGL by migrating radially inward to settle beneath the Purkinje cell layer to form the internal granule layer, resulting in the final laminar arrangement of the mature cerebellum.

The development of the cerebellar vasculature may also play an important role in the topography of preterm CBH and as such is worth reviewing. Early in embryogenesis, only the superior cerebellar arteries supply the cerebellar precursor.²⁵ The posterior inferior cerebellar artery (PICA) is visible in the human embryo only weeks later.²⁶ In addition the ultimate course of the PICA is the most highly variable among the cerebellar arteries. Macchi et al. speculated that for these reasons, the PICA may represent an acquired source of vascularization via angiotrophic vasculogenesis.²⁶ In adults the superior cerebellar artery perfuses the anterior lobe, while the PICA perfuses the posterior.²⁷ It is possible that as an acquired source of vasculogenesis the PICA is more susceptible to the cardiorespiratory perturbations typical of extreme prematurity, although this hypothesis is speculative and not currently supported by experimental evidence.²⁸

The posterior cerebellum not only has a distinct arterial supply, but it also has a separate venous system. The superior cortical surface of the cerebellum is drained by the superior vermian veins and the superior hemispheric veins, which empty into the great vein of Galen in the midline.²⁹^,³⁰ The posterior inferior cortical surface of the cerebellum is drained by the inferior hemispheric veins, which empty into the transtentorial sinuses, and the inferior vermian veins, which empty into the straight sinus directly or via the medial transtentorial sinuses. The significance of the differential venous drainage toward the topography of preterm CBH is unclear.

Cerebellar organization

The cerebellar cortex is organized into three rostrocaudally oriented compartments: the midline vermis, the paravermis, and the lateral cerebellar hemispheres. The cerebellar cortex of the cerebellar hemispheres connects to the brainstem via three paired cerebellar peduncles, via the cerebellar deep nuclei. The cerebellar deep nuclei are embedded in the white matter of the cerebellum and include, medially to laterally, the fastigial, interpositus (globose and emboliform), and dentate nuclei. The final cerebellar output arises from these deep cerebellar nuclei and exits the cerebellum via the superior and inferior peduncles. The cerebellum projects to specific cerebral destinations and receives input back from these same regions via the middle cerebellar peduncle, and thus forms reciprocal and functional circuits, or closed loops.³¹

The primary fissure divides the cerebellar hemispheres into the anterior and posterior lobes. The cerebellar hemispheres are further folded into multiple lobules.³² There are 10 lobules in the cerebellar cortex: lobules I–V represent the anterior lobe; lobules VI–IX the posterior lobe; and lobule X the flocculonodular lobe.³³ Lobule VII comprises almost 50% of the cerebellar cortex in humans and is subdivided into crus I, crus II, and VIIB (Fig. 5.4).³⁴^,³⁵

Fig. 5.4Segmented MRI T1-weighted images of the adult cerebellum. *Top panel:* Cerebellar lobules defined according to fissures with the left and right hemispheres containing a different set of labels in a sagittal (*left*) and coronal (*right*) section. *Bottom panel:* 3D surface representation of the cerebellar lobules. *Source:* (Adapted from Park MT, Pipitone J, Baer LH, et al. Derivation of high-resolution MRI atlases of the human cerebellum at 3T and segmentation using multiple automatically generated templates. *Neuroimage*. 2014;95:217–231.)

Functional topography

Accumulating evidence suggests that the role of the human cerebellum extends much beyond motor control to include nonmotor behaviors. This impression originates mainly from functional adult neuroimaging studies showing cerebellar involvement during a range of nonmotor tasks and clinical populations in whom cerebellar damage produces nonmotor deficits in cognition and behavior.³⁶

The cerebellum is reciprocally connected with sensorimotor and association regions of the cerebral cortex via the feedforward cortico-ponto-cerebellar and the feedback cerebello-thalamo-cortical pathways. Sensory and motor projections to the cerebellum reveal body maps in the anterior lobe of the cerebellum. The remaining lobules of the posterior lobe of the cerebellum are linked with the parietal and prefrontal association cortices.³⁷ Much of our knowledge around the functional organization of the human cerebellum comes from task-based and resting-state functional MRI (fMRI) studies. In task-based fMRI studies activations related to cognitive and emotional-affective processes are usually observed in the lateral posterior lobe.³⁸^,³⁹

Functional and structural imaging studies have revealed regional differences in neonatal and childhood development within the cerebellum. Recently, Herzmann et al. demonstrated via resting-state fMRI that cortico-cerebellar functional connectivity is well-established by term in even preterm newborns.⁴⁰ One important difference between functional organization of the cerebellum during the neonatal period relative to that of the adult was discovered in the somatomotor network. In the adult, the cerebellar sensorimotor network is mainly located in the anterior lobe.³⁹ In contrast to adult studies the study by Herzmann et al. did not find evidence for somatomotor representation in the anterior lobe of the cerebellum. The authors speculated that the somatomotor network and with it the anterior lobe of the cerebellum matures over the first years of life. This discrepancy between the neonatal and adult somatomotor representation in the cerebellum may herald discrepant deficits from similarly located injuries between the two age groups.

Adult cerebellar infarct

In the adult cerebellar functional topography is readily examined when the effects of cerebellar injury are studied in clinical populations. Infarcts affecting the superior cerebellar artery, which perfuses the anterior cerebellar lobe, are more likely to cause limb and gait ataxia. In contrast infarcts affecting the PICA, which perfuses most of the posterior lobe of the cerebellum, are more likely to result in the cerebellar cognitive affective syndrome (CCAS).²⁷^,⁴¹ In adults posterior lobe infarcts occur more often than anterior lobe infarcts.⁴²

The CCAS is characterized by deficits in language, visual-spatial function, executive function, and emotional-affective dysregulation following cerebellar injury. A recent voxel-based lesion symptom-mapping study reported that patients with cerebellar motor syndrome but no cognitive deficits had damage to the anterior lobe with spared posterolateral hemispheres; patients with CCAS but no motor deficits had an inverse pattern of injury.⁴³ These findings suggest good agreement between functional connectivity and lesion-deficit studies of the adult cerebellum.

Preterm cerebellar hemorrhage

Epidemiology and diagnosis with imaging

CBH is one of the classic forms of preterm brain injury and ranges in size from punctate hemorrhages to larger hemispheric and vermian hemorrhages.¹ The original reports of CBH were derived from postmortem studies.⁶^,⁷ In the mid-1990s routine posterior fossa imaging through the mastoid fontanel became more commonly applied to improve the ultrasonographic visualization of the posterior fossa in neonates.² These CBH visualized on the US have historically been associated with adverse neurodevelopmental outcomes as only larger CBH can be visualized on cranial US (Fig. 5.1).

The reported frequency of CBH in preterm neonates in contemporary studies varies and depends on whether diagnosis was made by cranial US or brain MRI (Fig. 5.5). Cranial US is only capable of detecting relatively large CBH that are greater than 4 mm in diameter; as such, reported rates of CBH diagnosed by cranial US are lower than those reported by brain MRI. For example, one prospective cohort study scanning preterm neonates with both serial cranial US and MRI reported that 7/140 (5%) had CBH on cranial US but 28/140 (20%) had CBH on MRI with susceptibility-weighted imaging (SWI).⁴⁴ The reported rates of CBH range from 14% to 37% in recent cohort studies of very preterm neonates using MRI with different sequences.⁹^,¹⁰^,¹²^,¹³^,⁴⁴ The specific MRI imaging protocol is also important, with SWI sequences possibly identifying more hemorrhages.²^,¹⁰^,¹²^,⁴⁵ SWI identifies iron deposition from degraded hemoglobin, and as such is highly sensitive for hemorrhage.