Abstract
Cerebellar hemorrhage is increasingly detected in both preterm and full-term newborns. This form of brain injury is more common in premature infants compared with term newborns. Cerebellar hemorrhage is now recognized as an important complication of preterm birth affecting up to 37% of infants born less than 33 weeks’ gestational age. Cerebellar hemorrhage can occur in isolation but more commonly occurs in combination with supratentorial brain injury and can range from small punctate hemorrhagic lesions to very large cerebellar hemorrhages. In this chapter, the neuropathology, pathogenesis, clinical features, diagnosis, prognosis, and management of preterm and term cerebellar hemorrhage is reviewed. Finally, this chapter highlights that cerebellar hemorrhage extends far beyond neuromotor impairments and plays a critical role in the long-term cognitive, behavioral, and social deficits.
Keywords
brain, cerebellum, magnetic resonance imaging (MRI), premature, ultrasonography (US)
Cerebellar hemorrhage has been increasingly detected in both preterm and full-term newborns in recent years. Currently, our understanding of cerebellar hemorrhagic injury and its long-term neurological sequelae has significantly changed, in large part due to increasing survival of critically ill infants and the greater availability and application of magnetic resonance imaging (MRI). Early studies reported a prevalence of cerebellar hemorrhage as high as 25% in premature infants at autopsy, usually associated with complicated births and a striking clinical presentation. Given the relative insensitivity to posterior fossa structures of cranial ultrasonography (US) through the anterior fontanel approach, it was not until the advent of focused mastoid foramen views that an unexpectedly high incidence of cerebellar lesions was noted in living premature infants (see later).
Cerebellar Hemorrhage: Preterm Infants
Prevalence
Cerebellar hemorrhage is now recognized as an important complication of premature birth and is more common among premature than term infants. Older neuropathological series reported an incidence among premature infants less than 32 weeks of gestation or less than 1500 g birth weight, or both, ranging from 15% to 25%. In contrast to these neuropathological reports, some large studies of living premature infants by computed tomography (CT) did not demonstrate cerebellar hemorrhage. The reason for the discrepancy may not relate simply to differences between dead and living populations. Flodmark et al. observed 15 cases of cerebellar hemorrhage at autopsy (all in premature infants) from 79 infants studied by CT for perinatal asphyxia. Among these 15 autopsy-proven cases, the hemorrhage was identified by CT in only one. (Ten of the lesions were considered to be “probably below the resolving power of the CT scanner.”) Similarly, in infants evaluated by US through the anterior fontanel, the identification of cerebellar hemorrhage is unusual. The advent of imaging through the mastoid fontanel, the thinnest region of the temporal bone at the junction of the squamosal, lambdoidal, and occipital sutures, has greatly facilitated accurate imaging of the posterior fossa in the newborn ( Figs. 23.1 and 23.2 ). Recent studies using this mastoid window report a high incidence of cerebellar hemorrhage in preterm infants. The largest reported study to date, based on use of this mastoid window in the evaluation of 1242 infants weighing less than 1500 g, showed an overall incidence of cerebellar hemorrhage of approximately 3% ( Table 23.1 ). However, the incidence varied markedly as a function of birth weight. Infants of less than 750 g of birth weight had the highest incidence (i.e., 8.7% overall, and notably, 17% in the last 2 years of the 5-year study) . Infants between 750 and 1499 g exhibited an overall incidence of approximately 2.7%. Indeed, in this large cohort, nearly 60% of all cerebellar hemorrhages were in the infants who weighed less than 750 g. Thus, cerebellar hemorrhage is particularly a lesion of the most immature infants. More recent data suggest that cerebellar hemorrhage in the preterm infant is even more prevalent, described in up to 19% of preterm infants of less than 32 weeks’ gestation. The addition of the mastoid fontanel window in cranial US improved the detection of cerebellar hemorrhage compared to detection by the anterior and posterior fontanel US views alone. With the mastoid view, abnormalities in the posterior fossa were detected in 71% of preterm infants but were missed using the anterior or posterior fontanel views. Notably, approximately half of small hemorrhagic cerebellar lesions (e.g., punctate hemorrhages) were undetected, even when the mastoid fontanel approach was used. When MRI is routinely performed in very preterm infants (<32 weeks gestational age), the incidence of cerebellar hemorrhage is still higher, ranging from 15% to 24%, but may be underdiagnosed if specific MRI sequences (e.g., susceptibility-weighted imaging) are not performed. With the latter approach and 3T-MRI, 37% of preterm newborns less than 33 weeks of gestation had cerebellar hemorrhage identified ( Table 23.2 ).
| BIRTH WEIGHT | INCIDENCE a |
|---|---|
| <750 g | 20/230 (8.7%) b |
| 750–999 g | 4/602 (0.7%) |
| 1000–1499 g | 11/410 (2.7%) |
| Total | 35/1242 (2.8%) |
a Incidence is expressed as n / N (%).
b Incidence in the last 2 years of the 5-year study period was 17%.
| Cranial ultrasound (with mastoid view) | 3%–9% a |
| Magnetic resonance imaging (MRI) | 15%–37% a,b |
| Sensitivity/specificity of routine CUS relative to MRI | 18%/100% c |
| Positive/negative predictive value of routine cranial ultrasound | 100%/84% c |
| Sensitivity/specificity of additional cranial ultrasound views relative to MRI | 45%/100% c |
| Positive/negative predictive value of additional cranial ultrasound views | 100%/89% |
a Data from Staggerda SJ, van Wezel-Meijler G. Cranial ultrasonography of the immature cerebellum: role and limitations. Semin Fetal Neonatal Med. 2016;21:295–304.
b Data from Gano D, Ho ML, Partridge JC, et al. Antenatal exposure to magnesium sulfate is associated with reduced cerebellar hemorrhage in preterm newborns. J Pediatr. 2016;178:68–74.
c Data from Staggerda SJ, Leijser LM, Wiggers-de Bruïne FT, van der Grond J, Walther FJ, van Wezel-Meijler G. Cerebellar injury in preterm infants: incidence and findings on US and MR imaging. Radiology . 2009;252:190–199.
Neuropathology
Four major categories of lesions have been described in infants with cerebellar hemorrhage ( Table 23.3 ). Primary cerebellar hemorrhage likely accounts for most cases of cerebellar hemorrhage in the preterm infant.
| Primary cerebellar hemorrhage |
| Venous (hemorrhagic) infarction |
| Extension into cerebellum of intraventricular or subarachnoid blood or both |
| Traumatic laceration of cerebellum or rupture of major veins or occipital sinus (with or without occipital diastasis) |
Primary cerebellar hemorrhage is the best studied of the destructive cerebellar lesions in premature infants. There is a broad spectrum in the severity of cerebellar hemorrhages reported, ranging from mild punctate lesions, focal unilateral lesions, to the less common and more extensive bihemispheric and vermian hemorrhages ( Figs. 23.3 to 23.5 ). The more extensive lesions range from partial inferomedial hemorrhage to near-total destruction of the cerebellum and may be associated with pontine hypoplasia on subsequent MRI ( Fig. 23.6 ). Recently, a cerebellar hemorrhage grading scheme was proposed ( Table 23.4 ). The hemorrhages are followed by cerebellar atrophy, detectable about 2 months later in 37%. Atrophy is focal in the unilateral lesions and more generalized in the bilateral lesions. Notably, reductions in contralateral cerebral volumes have been defined and likely reflect impaired remote transsynaptic trophic effects.
| Grade 1: Unilateral small punctate lesions (≤3 mm) |
| Grade 2: Bilateral small punctate lesions (≤3 mm) |
| Grade 3: Extensive unilateral lesions (>3 mm) |
| Grade 4: Bilateral extensive lesions (>3 mm) |
A recent neuropathologic study reported that the principal locus of cerebellar hemorrhage was the ventral aspect of the posterior lobe of the cerebellum and vermis. The cerebellar hemorrhages tended to be bilateral and involved the vermis (74%). Microscopically, the hemorrhages were located in the white matter or in the cerebellar cortex near the junction of the white matter and the internal granule cell layer and were associated with germinal matrix hemorrhage (95%) and pontosubicular necrosis (69%). More than half also had neuronal loss/gliosis in the inferior olivary nucleus and the dentate, which likely represents a transsynaptic degenerative process ( Fig. 23.7 ).
Cerebellar infarction is a recognized complication of extreme preterm birth. Distinction of hemorrhagic venous infarction from primary cerebellar hemorrhage can be very difficult, even at microscopic examination. Cerebellar infarcts typically involve the bilateral inferior parts of the cerebellar hemispheres, suggesting a vascular distribution in the territory of the posterior inferior cerebellar arteries, and often occur in combination with supratentorial white matter injury, suggesting a more generalized hypoxic-ischemic insult.
The extension of blood from intraventricular or subarachnoid spaces has been suggested as a cause of cerebellar hemorrhage . This notion was raised particularly by the studies of Donat et al. In 10 of their 20 cases of cerebellar hemorrhage, secondary dissection of blood into the cerebellum appeared to occur either from the fourth ventricle into the vermis or, less frequently, from the subarachnoid space into the cerebellar hemispheres. In these cases, massive hemorrhage into the lateral ventricles was the original source of the blood. This notion is supported by observations of a strong association of cerebellar hemorrhage with cerebral intraventricular hemorrhage (IVH). (Indeed, in the aforementioned study of 1242 premature infants who were less than 1500 g of birth weight and studied in vivo by US, about two-thirds of cases were associated with IVH.) Similarly, neuropathological studies also report that cerebellar hemorrhage is accompanied by IVH in 95% of cases. Hemosiderin deposition on the cerebellar surface from extraaxial blood can have toxic effects and result in injury to underlying structures (e.g., the external granule cell layer) and may impair the immature and rapidly developing cerebellum ( Chapter 4 ). However, a recent neuropathology report found no evidence for dissection of blood from the fourth ventricle or from the subarachnoid space that originates from IVH. Similarly, in a study of 73 preterm newborns with cerebellar hemorrhages, 70% (51/73) had no IVH and only 10% (7/73) had severe IVH.
The fourth potential mechanism of cerebellar hemorrhage, traumatic injury, with laceration of cerebellum or with rupture of cerebellar bridging veins or occipital sinus, often occurring with occipital osteodiastasis, was discussed in Chapter 22 (see the section on subdural hemorrhage). This category may be important to some term infants with hemorrhage. In the preterm infant, the ventral posterior loci of cerebellar hemorrhage is in a distribution that corresponds to the posterior inferior veins that drain the inferior cerebellar hemispheres into the transverse sinus, and the inferior vermis into the confluens. The compliant skull of the preterm infant would render it vulnerable to compression of the occipital region by external forces, displacing the squamous portion of the occipital bone and distorting the venous sinuses at the confluens, thereby increasing venous pressure, and preferentially affecting the ventral cerebellum. This mechanism of injury raises the possibility that cerebellar hemorrhage can arise from a venous source.
The neuroimaging of the loci of the hemorrhages within the cerebellum in the small premature infant includes both the hemisphere and the vermis. The lesions tend to be focal and localized. Approximately 70% of the lesions are localized to one cerebellar hemisphere, and 20% are localized to the vermis ( Table 23.5 ). Smaller lesions have included both subpial and subependymal locations, which are the sites of the germinal matrices in the external granule cell layer and subependymal zones, respectively. More recently, very small or punctate cerebellar hemorrhagic lesions have been reported on MRI ( Figs. 23.8 and 23.9 ). The more widespread use of MRI and the newer MRI techniques, such as susceptibility-weighted imaging, have increased the detection of these punctate lesions, which are difficult to detect by cranial US. In large lesions, the cerebellar cortex and underlying white matter are destroyed. Notably, the neuropathological study by Haines et al. showed that cerebellar hemorrhage was mulitfocal with lesions of variable size and histopathological age, suggesting that cerebellar hemorrhage may develop as a series of recurrent hemorrhagic episodes occurring over a period of time.
| LOCUS | OCCURRENCE (%) |
|---|---|
| Unilateral hemisphere | 71 |
| Vermis | 20 |
| Both hemispheres and vermis | 9 |
| Isolated a | 23 |
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