Version May 2024
INTRODUCTION — Cerebellar injury is a serious complication of preterm birth with subsequent risk for neurodevelopment impairment [1-8].
In this topic, we will describe normal cerebellar structure and fetal development, and cerebellar disorders including malformations and acquired injury.
Neonatal cerebellar hemorrhage, germinal matrix-intraventricular hemorrhage, cystic periventricular leukomalacia and hypoxic-ischemic brain injury are discussed in greater detail separately:
●(See "Neonatal cerebellar hemorrhage".)
●(See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)
●(See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)
●(See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy" and "Etiology and pathogenesis of neonatal encephalopathy", section on 'Hypoxic-ischemic injury' and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'White matter injury'.)
●(See "Etiology and pathogenesis of neonatal encephalopathy".)
NORMAL CEREBELLAR FUNCTION, ANATOMY AND DEVELOPMENT
Function — The cerebellum is well known for controlling motor functions involved with balance, position, tone, and locomotion. Additional roles of the cerebellum have been identified, including cognition, language, emotion, behavior, working memory, and executive function [9-12]. (See "Overview of cerebellar ataxia in adults", section on 'Clinical syndromes'.)
Anatomy — The cerebellum is located in the posterior fossa and, in adults, comprises 10 percent of the brain volume. It is connected to both the brainstem and the cerebrum via the cerebellar peduncles. The cerebellum has two hemispheres, joined together by a longitudinal depression running down the midline of both hemispheres called the vermis (figure 1). The cerebellum is divided into three lobes: the anterior, posterior, and flocculonodular lobes, separated by two fissures. The primary fissure separates the anterior and posterior lobes, and the posterolateral fissure separates the posterior and flocculonodular lobe. The mature cerebellum has three separate layers: the cortex, the underlying white matter, and the deep nuclei. The cortex is subdivided into three distinct layers: the molecular layer, Purkinje cell layer, and granule cell layer.
The Purkinje cells are the most important cellular components of the cerebellar cortex. They have very large cell bodies and enormous fan-shaped dendritic trees that fill the molecular layer. The Purkinje cells are the only efferent projection neurons of the cerebellar cortex; all other neurons in the cerebellar cortex are local circuit neurons [13,14]. The two main afferent pathways sending information to the cerebellar cortex are the climbing and mossy fiber systems. The climbing fibers originate from the inferior olivary nucleus and synapse directly with the Purkinje cells. The mossy fibers originate from nuclei in the spinal cord and brain stem and the cerebellar nuclei. They synapse with the granular cells and thus indirectly with the Purkinje cells (image 1) [13,15,16].
Below the cortical layers lies the cerebellar white matter, which contains a dense network of fiber tracts. The cerebellar nuclei are embedded in the center of the white matter and contain the neurons that transmit the final output of the cerebellum [15]. The cerebellar nuclei relay information from the cerebellar cortex to the thalamus (image 1) [16].
Development — The human cerebellum is one of the first structures in the brain to differentiate, beginning in the fourth week of gestation, but one of the last to mature extending to about 20 months postnatally. The fastest growth occurs in the second half of gestation during a period of active migration and differentiation of cells from the two proliferative zones (the fourth ventricular germinal matrix and the rhombic lips).
●From the fourth ventricular germinal matrix, inhibitory GABAergic neurons proliferate, followed by radial migration into the deep cerebellar nuclei and the Purkinje cell layer.
●From the germinal matrix of the rhombic lips, accelerated proliferation and tangential migration of the precursor granule cells results in coverage of the complete cerebellar surface by the third trimester. This external granular layer develops an outer zone of proliferation and an inner zone of postmitotic cells, which subsequently migrate radially through the Purkinje cell layer to form the internal granular layer [17,18].
During migration, the granule cells form axons, the parallel fibers that connect with the dendrites of the Purkinje cells. After arrival in the internal granular layer, they connect with mossy fibers that ascend from the pontine nuclei (image 1) [19].
These processes result in the development of the cerebellar vermis and hemispheres, establishment of neuronal connectivity, and a more than five-fold increase of cerebellar volume between 20 and 40 weeks' gestation (image 1) [15,16,19,20].
PREMATURITY AND RISK OF CEREBELLAR INJURY — Prematurity is the most important risk factor for cerebellar injury. The risk of injury increases with decreasing gestational age (GA). In one small autopsy study of 19 preterm infants with cerebellar hemorrhage, the mean GA was 25 weeks, at which time the cerebellum would have only reached 20 to 25 percent of its expected term volume [21].
It is postulated that the extrinsic injury not only causes direct damage but also disrupts the expected growth and development of the cerebellum (hypoplasia) and its neural connectivity [22]. This theory is supported by imaging studies that report subsequent smaller than expected cerebellar volumes [23-27]. It remains unclear whether the underlying mechanism is due to atrophy or disruption of growth (hypoplasia), or a combination of the two.
CEREBELLAR MALFORMATIONS — Primary malformations are defined as non-progressive, congenital morphologic anomalies of organs or body parts due to an alteration of the primary development. Cerebellar primary malformations are detected by brain imaging, typically performed prenatally and repeated postnatally (see "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Posterior fossa abnormalities'). They may occur in isolation, together with other brain abnormalities, or as part of a syndrome involving other organ systems. In many cases, there is a known genetic cause [28,29].
However, similar morphologic findings (eg, cerebellar hypoplasia) may be caused by either congenital malformations or disruptions of normal development due to extrinsic factors (eg, hemorrhage, infection, and stroke). A disruption is defined as a nonprogressive, congenital morphologic anomaly due to the breakdown of a body structure that had a normal developmental potential.
Although challenging, distinguishing between a malformation and a disruption is important for genetic and prognostic counseling [29,30]. (See 'Distinguishing between primary malformation versus injury' below.)
Postnatal findings in children with cerebellar malformations are generally non-specific, may only become apparent during infancy, and include hypotonia, motor dysfunction (ataxia and spasticity), nystagmus, decreased visual attention, apnea, feeding difficulties, and seizures [29,30].
There are numerous cerebellar malformations such as the following, and cerebellar malformations are part of numerous genetic disorders and syndromes [19,28,29]:
●Cerebellar hypoplasia.
●Cerebellar hyperplasia.
●Isolated vermian hypoplasia.
●Dandy-Walker malformation and Dandy-Walker variant. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Dandy-Walker malformation'.)
●Pontocerebellar hypoplasia.
●Joubert syndrome (molar tooth malformation) characterized by cerebellar vermis hypoplasia or dysplasia; long, thick, elevated superior cerebellar peduncles; a thin midbrain-hindbrain junction; and a deep interpeduncular fossa producing the "molar tooth sign" on axial MRI (image 2). (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome'.)
●Cerebro-ocular dysplasia or Walker-Warburg syndrome (WWS). (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Walker-Warburg syndrome'.)
●Rhombencephalosynapsis (RES) is characterized by cerebellar malformation in which the vermis is deficient or absent and the hemispheres are fused across the midline.
●PHACE syndrome (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies). (See "PHACE syndrome".)
CEREBELLAR INJURY — Due to its rapid and prolonged fetal development, the cerebellum is particularly vulnerable for injury. Injury may occur prenatally or postnatally. Significant injury may result in long-term neurodevelopmental impairment. The following conditions have been directly or indirectly associated with damage to the developing cerebellum [22]:
●Preterm birth (see 'Prematurity and risk of cerebellar injury' above)
●Antenatal or neonatal cerebellar hemorrhage
●Cerebellar infarction
●Hypoxic-ischemic injury
●Congenital infection (eg, cytomegalovirus, Zika virus, rubella) (see "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Neuroimaging' and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate", section on 'Neuroimaging')
●Postnatal sepsis and meningitis [31] (see "Bacterial meningitis in the neonate: Neurologic complications")
●Drug and environmental exposures [28,31-33]
●Certain metabolic conditions (eg, peroxisomal and mitochondrial disorders) (see "Peroxisomal disorders")
Cerebellar hemorrhage — Cerebellar hemorrhage is one of the major and most frequent causes of neonatal cerebellar injury [34-36]. It is discussed in great detail separately. (See "Neonatal cerebellar hemorrhage".)
Cerebellar infarction — Cerebellar infarction, first described in 1997, is defined as a lesion with a well-defined boundary and no evidence of hemorrhage and is present in the distribution of one of the cerebellar arteries while the remainder of the cerebellum is normal [37]. The area of infarction typically involves the inferior cerebellum, which is supplied by the posterior inferior cerebellar arteries, although other cerebellar tissue may be affected [22].
Published case series from the same research group have reported severe cerebellar underdevelopment or atrophy detected by magnetic resonance imaging (MRI) in children with cerebral palsy who were born extremely preterm (GA <28 weeks). They based their conclusion on the localization of the abnormalities in the territory of the posterior inferior cerebellar arteries and the coexistence with periventricular leukomalacia, suggesting primary infarction rather than primary hemorrhage with resulting venous infarction [38-40]. However, there was no available neonatal imaging of the cerebellum at the time of acute injury. In addition, in our experience we have often observed extensive cerebellar atrophy and destruction following large cerebellar hemorrhage, but we have only rarely encountered primary cerebellar infarction.
The clinical impact of primary cerebellar infarctions remains uncertain, as it is challenging to differentiate primary infarction from (partial) cerebellar destruction due to a primary hemorrhage. In preterm infants, serial cranial ultrasound examinations and MRI (including susceptibility-weighted imaging [SWI] that is particularly sensitive for the detection of blood products) provide information to distinguish between the two conditions and determine the relative frequency and impact of cerebellar infarction [23,35].
Hypoxic-ischemic injury — In high-risk, full-term neonates, widespread cerebellar injury may occur after severe hypoxic-ischemic encephalopathy (image 3) [32,41,42]. Although the cerebellum is often relatively spared [43], hypoxic-ischemic conditions may directly injure the cerebellum and are associated with small cerebellar volumes in survivors [41,42]. Neonatal hypoxic-ischemic encephalopathy is discussed in detail separately. (See "Etiology and pathogenesis of neonatal encephalopathy", section on 'Hypoxic-ischemic injury'.)
Infection — Antenatal infection due to cytomegalovirus and Zika virus, and less frequently due to rubella and varicella viruses, have been associated with global cerebellar hypoplasia [28,44]. Other neuroimaging findings of antenatal infections include intracranial calcifications, ventriculomegaly, white matter signal changes, and neuronal migrational disorders [30,45]. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Neuroimaging' and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate", section on 'Neuroimaging'.)
Acute cerebellar injury in full-term infants with severe infections (mainly group B streptococcal [GBS] sepsis and meningitis) has also been observed [32].
Drug and environmental exposures — Several agents have been associated with damage to the developing cerebellum, such as alcohol, free iron and certain drugs, including postnatal corticosteroids and opiates [28,36,45-48]. It is also postulated that hemosiderin deposits and free iron in the subarachnoid space following supratentorial hemorrhage may cause direct damage to the immature cerebellum, resulting in underdevelopment of the anatomic cerebellar components and neural connections (image 4) [19,36].
Metabolic disorders — Certain inborn errors of metabolism, such as oxidative phosphorylation and peroxisomal disorders and carbohydrate deficient glycoprotein syndrome, are associated with cerebellar abnormalities, including hypoplasia [31,45,49-51]. Structural anomalies can occur in Zellweger syndrome, pyruvate dehydrogenase complex deficiency, and other mitochondrial diseases [33,45,52,53]. (See "Peroxisomal disorders".)
NEUROIMAGING — Advances in fetal and neonatal neuroimaging have increased awareness of cerebellar abnormalities. Neonatal cerebellar disorders can be detected with ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT). Ultrasonography is the preferred technique for serial brain imaging in high-risk neonates. It is a portable imaging modality that can be performed at the bedside with little disturbance to the infant without ionizing radiation, and it is less expensive than the other modalities [54].
Cranial ultrasound — The introduction of additional acoustic windows (eg, mastoid fontanel) beyond the routine use of the anterior fontanel has improved visualization of the neonatal posterior fossa structures [23,32,54-58]. Routine ultrasound using the anterior fontanel window enables detection of the majority of clinically relevant supratentorial lesions [59]. However, evaluation of infratentorial structures including the cerebellum is often suboptimal due to the large distance between the transducer and the posterior fossa and the echogenic tentorial area that hampers visualization of the posterior fossa structures. The use of the mastoid fontanel as an additional window overcomes these difficulties (figure 2) [23,54]. Transnuchal ultrasound, using the foramen magnum as acoustic window, is another valuable technique to visualize the cerebellum and monitor cerebellar growth (image 5) [60].
Mastoid fontanel images of the posterior fossa are performed in transverse planes while scanning from superior to inferior and in coronal planes scanning from anterior to posterior. The brain stem, cerebellar hemispheres, vermis, fourth ventricle, and cisterna magna can be visualized by this approach, and the transcerebellar diameter (TCD) can be measured to monitor cerebellar growth (image 6 and image 7 and image 8) [23,54,55,61,62].
Several studies have confirmed that the addition of mastoid fontanel views leads to a better detection of cerebellar abnormalities, both in preterm and full-term newborn infants [32,34,35,56,63,64]. In two case series, the routine use of mastoid views allowed detection of cerebellar lesions that were missed when only the anterior fontanel was used [35,56]. However, ultrasound was less sensitive than MRI in identifying small punctate cerebellar lesions [35].
Magnetic resonance imaging (MRI) — Compared with ultrasound, MRI has the advantage of providing more detailed, quantitative, and functional imaging. In particular, MRI can identify injury due to hypoxia-ischemia, postnatal infection, and small punctate cerebellar hemorrhage, which may be missed by ultrasound [32,35] (see "Neonatal cerebellar hemorrhage", section on 'Magnetic resonance imaging (MRI)'). As MRI provides a more detailed and complete visualization of the whole brain, it contributes importantly to accurate diagnosis and prognosis in infants with cerebellar malformations and disruptions. However, its cost and the need to transport often seriously ill and/or preterm infants to the MRI suite preclude its use as the primary neuroimaging modality in the acute stage. In preterm infants with postnatally acquired cerebellar injury, MRI is best performed at term equivalent age, as the infants are generally clinically more stable and more information can be obtained on cerebellar and cerebral growth, maturation, and abnormalities.
Besides the serial ultrasound examinations that we perform in all high-risk neonates, we perform additional MRI examinations in preterm neonates before term equivalent age only if findings that would impact management are suspected. Term equivalent MRI is performed in preterm neonates with significant supra- and/or infratentorial abnormalities, as it helps to define the exact origin, location, and extension of abnormalities and thus to prognosticate and to counsel parents [54,59]. In addition, we perform MRI scans in all high-risk (near) term neonates with neurological symptoms and in all (near) term neonates who underwent hypothermia treatment for perinatal asphyxia [54].
Volumetric MRI can detect impairment of cerebellar growth as an indirect measure of cerebellar injury. Moreover, cerebellar injury itself may also have a remote effect on the development of other brain structures. On subsequent later MRI scans of infants with cerebellar injury, a flattening of the pontine base can be seen [65]. In volumetric MRI studies, an underdevelopment of specific cortical areas functionally connected to the affected cerebellar hemisphere (cerebello-cerebral diaschisis) can be observed [66,67]. Therefore, in a research setting, MRI may provide further insight into the neurodevelopmental consequences of early cerebellar injury [66,68,69].
Computed tomography (CT) — Although cerebellar disorders can be visualized by CT, CT has no additional diagnostic value when compared with ultrasound and MRI [70]. It requires transportation to the scanner and exposes the patient to ionizing radiation.
DIAGNOSIS — Neuroimaging is used to diagnose cerebellar malformations and injury.
Prenatal diagnosis — Prenatal ultrasound, and in some cases magnetic resonance imaging (MRI), are used to evaluate the fetal central nervous system including the cerebellum. Prenatal neuro-imaging is discussed separately. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly".)
Postnatal diagnosis — Cranial ultrasonography is most commonly used to diagnose cerebellar pathology. We perform serial ultrasound examinations in all high-risk neonates from birth until discharge or term equivalent age.
Ultrasonography is the preferred imaging modality because of its ease of portability (bedside imaging), lack of ionizing radiation, and improved sensitivity using additional acoustic windows to the anterior fontanel such as the mastoid fontanel (figure 2 and image 6 and image 7) (see 'Cranial ultrasound' above). Mastoid fontanel ultrasound imaging allows the detection of most neonatal cerebellar abnormalities and is used in our centers when scanning neonates at-risk for cerebellar injury [23,32,34,35,54-58]. The American Academy of Pediatrics recommends that standard neonatal cranial ultrasonography includes views through the anterior and mastoid fontanelles [63]. The additional imaging through the mastoid fontanelles was recommended because of the increasing evidence that the cerebellum is a frequent site of neonatal injury. (See 'Cranial ultrasound' above and "Neonatal cerebellar hemorrhage", section on 'Preterm infants' and "Neonatal cerebellar hemorrhage", section on 'Cranial ultrasound' and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'Screening'.)
Distinguishing between primary malformation versus injury — Antenatally or postnatally acquired cerebellar injury may mimic primary cerebellar malformations, as both may result in cerebellar hypoplasia and other developmental disruptions. Distinction between primary cerebellar malformations versus abnormality due to injury may be of clinical importance, as it can have consequences for treatment, prognosis and genetic counseling. Therefore, in the case of cerebellar anomalies present at birth, additional diagnostic evaluation in addition to neuroimaging may be necessary to clarify the underlying etiology [23,28,29]. However, this is typically a challenging undertaking, and in these cases, referral to clinicians and geneticists with expertise in the evaluation and care of neonates with cerebellar abnormalities is warranted.
OUTCOME — Traditionally, the cerebellum was thought to be mainly involved in motor control, and it was assumed that the most important consequences of neonatal cerebellar lesions were problems with coordination of balance, gait, extremity and eye movements, and dysarthria. In surviving preterm infants, a review of outcome studies described a high prevalence of long-term neurodevelopmental disabilities due to direct cerebellar injury that included not only poor motor development but also cognitive and language impairments and socialization and behavioral difficulties [2,7,71]. These findings are similar to those described in adults and older children with cerebellar injury with cognitive and behavioral abnormalities, including impairments of executive function and visual spatial function, language difficulties, impaired attention, and behavioral disorders [7,72]. This combination of cognitive disturbances leads to a general lowering of intellectual function referred to as posterior fossa syndrome or cerebellar cognitive affective syndrome (see "Treatment and prognosis of medulloblastoma", section on 'Posterior fossa syndrome'). Cerebellar injury may thus play an important and previously under-recognized role in the cognitive, learning, and socio-behavioral problems known to affect survivors of extreme preterm birth.
SUMMARY AND RECOMMENDATIONS
●The cerebellum not only controls motor functions involved with balance, position, tone, and locomotion, it also plays a role in cognitive, language, emotion, behavior, working memory, and executive function. (See 'Normal cerebellar function, anatomy and development' above.)
●Cerebellar injury is increasingly recognized as a serious complication of preterm birth with subsequent risk for long-term neurodevelopment impairment. The cerebellum is particularly vulnerable for injury in preterm and severely ill (near) term infants because of its prolonged and accelerated fetal development, especially in the second half of gestation that extends to 20 months postnatally. The risk of injury increases with decreasing gestational age. (See 'Prematurity and risk of cerebellar injury' above.)
The following conditions are associated with neonatal cerebellar injury (see 'Cerebellar injury' above):
•Preterm birth
•Antenatal or neonatal cerebellar hemorrhage
•Cerebellar infarction
•Hypoxic-ischemic injury
•Congenital or postnatal infection
•Drug and environmental exposures
•Metabolic disorders
●Primary cerebellar malformations are non-progressive, congenital morphologic anomalies of organs or body parts due to an alteration of the primary development. They may have similar morphologic findings (eg, cerebellar hypoplasia) detected on neuroimaging as those caused by cerebellar injury. Distinguishing between the two is important for genetic and prognostic counseling. (See 'Cerebellar malformations' above and 'Distinguishing between primary malformation versus injury' above.)
●Neonatal cerebellar disorders can be detected with ultrasound and magnetic resonance imaging (MRI). We perform serial ultrasound examinations in all high-risk neonates from birth until discharge or term equivalent age. Ultrasonography is the preferred technique for this; it is a portable imaging modality that can be performed at the bedside with little disturbance to the infant without ionizing radiation and is less expensive than the other modalities. The addition of mastoid fontanel views to the routine use of anterior fontanel windows has led to improved detection of cerebellar abnormalities. (See 'Neuroimaging' above.)
●Diagnosis of cerebellar primary malformations or injury is made by neuroimaging. For neonates at-risk for cerebellar injury, ultrasonography should include imaging through the mastoid fontanel. (See 'Neuroimaging' above and 'Diagnosis' above.)
●Reported long-term neurodevelopmental disabilities due to direct cerebellar injury in survivors born preterm include motor, cognitive, and language impairments, as well as socialization and behavioral difficulties. (See 'Outcome' above.)
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