e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 3 9 7 – 4 0 7

Official Journal of the European Paediatric Neurology Society

Review article

Morphological spectrum of prenatal cerebellar disruptions

Andrea Porettia, Daniela Prayerb, Eugen Boltshausera,*aDepartment of Paediatric Neurology, University Children’s Hospital of Zurich, Zurich, SwitzerlandbDepartment of Neuroradiology, Medical University of Vienna, Vienna, Austria

a r t i c l e i n f o

Article history:

Received 11 May 2008

Received in revised form

25 June 2008

Accepted 1 September 2008

Keywords:

Cerebellar disruption

Cerebellar hypoplasia

Unilateral cerebellar hypoplasia

Cerebellar agenesis

Vanishing cerebellum

Neuroimaging

* Corresponding author. University Children’44 266 7163.

E-mail address: Eugen.Boltshauser@kispi1090-3798/$ – see front matter ª 2008 Europdoi:10.1016/j.ejpn.2008.09.001

a b s t r a c t

There is increasing evidence that the cerebellum is susceptible to both prenatal infections

and haemorrhages as well as being vulnerable in extremely preterm babies, but not to

perinatal and postnatal hypoxic-ischaemic injuries. Starting with the imaging appearance

we describe and illustrate a spectrum of prenatal cerebellar disruptions: cerebellar agen-

esis; unilateral cerebellar hypoplasia; unilateral cerebellar cleft; global cerebellar hypo-

plasia; vanishing cerebellum in myelomeningocele; and disruption of cerebellar

development in preterm infants. We discuss neuroradiological characteristics, possible

disruptive events, and clinical findings in the different morphological patterns. Remark-

ably, the same disruptive agent can cause different neuroradiological patterns, which

appear likely to represent a morphological spectrum. The analysis of imaging patterns is

crucial in recognising cerebellar disruptions. Recognition of cerebellar disruptions and

their differentiation from cerebellar malformations is important in terms of diagnosis,

prognosis, and genetic counselling.

ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3982. Case selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3983. Prenatal cerebellar disruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

3.1. Global cerebellar hypoplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3983.2. Unilateral cerebellar hypoplasia or aplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3993.3. Cerebellar agenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4013.4. Unilateral cerebellar cleft . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4013.5. Vanishing cerebellum in myelomeningocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4023.6. Disruption of cerebellar development in

preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4034. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4035. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

s Hospital, Steinwiesstras

.uzh.ch (E. Boltshauser).ean Paediatric Neurology

se 75, CH-8032 Zurich, Switzerland. Tel.: þ41 44 266 7330; fax: þ41

Society. Published by Elsevier Ltd. All rights reserved.

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 3 9 7 – 4 0 7398

1. Introduction

The high spatial resolution, the excellent tissue contrast, and

the multiplanar imaging offered by magnetic resonance

imaging (MRI) have facilitated a more accurate and precise

identification and description of cerebral and cerebellar

developmental abnormalities in children.1 These abnormali-

ties include both malformations and disruptions.

Malformations are defined as morphological defects of an

organ, part of an organ, or a larger region of the body resulting

from an intrinsically abnormal developmental process.2

Cerebellar malformations such as Dandy–Walker malforma-

tion,3,4 Joubert syndrome,5,6 or rhombencephalosynapsis7,8

have been extensively described. Furthermore, classification

schemes of cerebellar malformations have been proposed

combining imaging with molecular biology.9,10

Disruptions are defined as morphological defects of an

organ, part of an organ, or a larger region of the body resulting

from an extrinsic breakdown of, or an interference with, an

originally normal developmental process.2 It may well be that

genetic factors contribute to the susceptibility to disruptions.

Good examples of disruptions are twin disruption

sequence,11 amnion rupture sequence,12 and hydranence-

phaly.13 Intrauterine death of one foetus in a monochorionic

twin pregnancy is associated with high morbidity and

mortality in the surviving co-twin. Alternatively, acute blood

loss into the dying twin through placental anastomoses may

result in hypotension and hypoxic-ischaemic damage to

cerebral and visceral tissue in the surviving twin. The ensuing

clinical picture often results primarily from the cerebral lesions

and is characterised by severe neurological symptoms.11

Amnion rupture sequence represents a disruption sequence

characterised by major anomalies of the craniofacial region,

body wall, and limbs. The mechanism involved in the

pathogenesis may be vascular disruption,12 which includes

ischaemic or haemorrhagic lesions. Hydranencephaly is

characterised by a virtual absence of the cerebral hemispheres,

leaving only glial membranous sacs filled with cerebrospinal

fluid. The aetiology includes several disruptive factors such as

vascular lesions or infection.13

To date, cerebellar disruptions have received less attention

in the literature than cerebellar malformations. Therefore we

have reviewed our patients and published cases of cerebellar

disruptions in an attempt to facilitate their characterisation

on the basis of the morphological pattern and the postulated

aetiology.

2. Case selection

This study addresses only prenatal cerebellar disruptions with

the exception of neonatal cerebellar disruption related to very

preterm neonates. Therefore cerebellar disruptions occurring

outside of this period, such as neonatal cerebellar haemor-

rhages or profound perinatal hypoxia, have not been included.

The conditions listed in Section 3 have been compiled from

the following sources: for many years we have been collecting

patients with cerebellar disruptions in our clinical practice

and from consultations for ‘‘second opinions’’; we have

consulted textbooks on cerebellar and neuroembryological

disorders as well as on neuroimaging; we have collected

reports in the literature relating to disruptions with cerebellar

involvement; and Pubmed was searched with appropriate key

words.

However, there are several potential problems and limita-

tions with this way of compilation:

(a) cerebellar involvement compatible with a cerebellar

disruption has been reported in texts but the description of

the patient’s history and neuroimaging is sometimes poor

and illustrations are lacking;

(b) particular disorders may be due to a ‘‘malformation’’ as

well as to a ‘‘disruption’’ (e.g. cerebellar cortical dysplasia,

cerebellar hypoplasia);

(c) prenatal MRIs demonstrating a disruptive lesion have only

been reported in very few cases; and

(d) in our cases, a prenatal diagnosis was also only made in

a few cases.

3. Prenatal cerebellar disruptions

3.1. Global cerebellar hypoplasia

The term ‘‘global cerebellar hypoplasia’’ describes a cere-

bellum of reduced volume. On midsagittal sections the vermis

is small but retains a (near) normal shape. Owing to the

reduction in size of the cerebellum, the subarachnoid spaces

are passively enlarged.

Global cerebellar hypoplasia is a heterogeneous condition

and can be due to a variety of causes, both malformation and

disruptions.14 Typical malformations causing global cerebellar

hypoplasia include chromosomal aberrations such as triso-

mies 9, 13, and 18, several metabolic disorders such as

congenital disorders of glycosylation,15 prenatal exposure to

teratogenic drugs such as anticonvulsant drugs16 or cocaine,17

isolated genetic cerebellar hypoplasias,18–22 complex genetic

malformations or migration disorders such as lissence-

phaly,23,24 some types of congenital muscular dystrophies,25–27

and pontocerebellar hypoplasias.28–30

Cerebellar hypoplasia can also be seen following prenatal

infections, particularly cytomegalovirus (CMV), representing

a disruption.31,32 MRI findings in congenital CMV include

cerebellar hypoplasia, enlarged ventricles, abnormal white

matter signal intensity representing delayed or deficient

myelination, intracranial calcification, gyral anomalies, and

cysts in the anterior portion of the temporal lobes (Fig. 1).31–33

It is possible to determine the timing of the infection on the

basis of the different gyral abnormalities. If lissencephaly is

present, the infection is more likely to have occurred before

16–18 weeks, whereas in the case of polymicrogyria the

infection probably occurred between 18 and 24 weeks of

gestation.32 However, the spectrum of abnormalities is wide,

ranging from normal anatomy to severe cerebellar hypoplasia.

The severity of the cerebellar abnormalities usually correlates

with the timing of the infection during the pregnancy. Indeed,

Steinlin et al. did not detect cerebellar involvement in seven

patients with less prominent clinical signs (microcephaly,

Fig. 1 – Congenital cytomegalovirus infection: (A) axial CT on day 2 showing ventriculomegaly, cerebellar hypoplasia, and

periventricular hyperdensities representing calcification; (B) axial T2-weighted MRI at the age of 14 months revealing

cerebellar hypoplasia as well as hyperintensity of the white matter and polymicrogyria of both temporal lobes; (C) coronal

T2-weighted MRI demonstrating global cerebellar hypoplasia, enlarged lateral ventricles, hyperintensity of the white

matter, and cortical gyral anomalies such as pachygyria and polymicrogyria; (D) axial T2-weightd image demonstrating

enlarged lateral and third ventricles, hyperintensity of the white matter, cortical gyral anomalies such as pachygyria and

polymicrogyria, and periventricular hypointensities suggestive of calcification.

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 3 9 7 – 4 0 7 399

hearing deficits, and minor neurological handicap), very likely

due to a CMV infection in the third trimester.34

In animals, cerebellar hypoplasia has been reported in

various species following prenatal infections due to different

viruses, such as Aino virus in calves or parvovirus in cats.35,36

3.2. Unilateral cerebellar hypoplasia or aplasia

Unilateral cerebellar hypoplasia seems to represent a spectrum

ranging from ‘‘complete’’ aplasia (unilateral absence of one

cerebellar hemisphere) (Fig. 2) to subtotal or less pronounced

(asymmetric) hypoplasia (Fig. 3). The characteristic MRI finding

is an asymmetry of the cerebellar hemispheres ranging from

aplasia to mild hypoplasia of a cerebellar hemisphere. Typi-

cally, the pons is asymmetric with contralateral volume

reduction (Figs. 2 and 3). The designation unilateral cerebellar

aplasia or hypoplasia is a descriptive term but lacks a patho-

genetic explanation.

Increasing experience with prenatal ultrasound37–42 and

foetal magnetic resonance imaging43,44 has proved that

unilateral cerebellar aplasia or hypoplasia is of prenatal (rep-

resenting a disruption) and not perinatal origin and it has

repeatedly been documented as early as 20–24 weeks of

gestation.37,44 We found a hypoplasia of the right cerebellar

Fig. 2 – Total aplasia of the right cerebellar hemisphere in

a 4 year old child found in investigation of a developmental

delay: coronal T2-weighted MRI showing complete

absence of the right cerebellar hemisphere.

Fig. 3 – Hypoplasia of the right cerebellar hemisphere in

a 12 year old boy with headaches: axial T1-weighted MRI

revealing an asymmetry of the cerebellar hemispheres

with hypoplasia of the right cerebellar hemisphere and

asymmetry of the pons with contralateral volume

reduction.

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hemisphere in a foetus at 20 weeks of gestation (Fig. 4). These

lesions are due to a unilateral disruptive effect including both

foetal ischaemic infarctions45 as well as foetal haemor-

rhages.39–44 Afadapa and Elsapagh reported a case of a woman

with a failed termination of her pregnancy with misoprostol at

10 weeks of gestation.45 The pregnancy was continued and at

17 weeks gestation a hypoplasia of the right cerebellar hemi-

sphere was diagnosed. The pregnancy was then interrupted at

23 weeks of gestation. The follow-up of children born to

mothers who had misused misoprostol for attempted termi-

nation of pregnancy showed transverse limb defects and

a Moebius-like syndrome.46 These findings are attributable to

vascular disruption (probably ischaemic), perhaps due to

uterine contractions induced by this drug. Therefore it is likely

that unilateral cerebellar hypoplasia is also the result of an

ischaemic disruptive effect. Cerebellar haemorrhages can be

a complication of CMV infection,41 or be caused by bleeding

from a congenital vascular defect such as a cavernous hae-

mangioma,38,42 or by a trauma,47,48 and may be related to

a haemorrhagic transformation of an infarction,44,49 but in

most cases the cause remains obscure.39,40,43 Although

a foetal cerebellar haemorrhage was documented, haemosi-

derin deposition was not seen on follow-up imaging in any of

the cases. To our knowledge, the absence of haemosiderin

deposition on follow-up imaging is well recognised in cere-

bellar haemorrhage. Indeed, in preterm infants with cere-

bellar haemorrhage haemosiderin is no longer seen from

6 weeks after its occurrence (F.M. Cowan and M.A. Rutherford,

personal communication). This is probably due to the

permeability of the blood–brain barrier to haemosiderin-

loaded macrophages.

Occasionally, unilateral cerebellar hypoplasia can be

a coincidental finding in children with complex brain mal-

formations such as holoprosencephaly (Fig. 5). A disruption

such as an ischaemic lesion can also cause an unilateral

cerebellar hypoplasia. In these cases an MRI was performed

because of clinical findings of supratentorial dysfunction

(Fig. 5). Consequently, the additional cerebellar abnormalities

were unexpected. Unilateral cerebellar hypoplasia has also

been reported in association with some syndromes such as

Moebius’ syndrome50 or Goldenhar syndrome,51 which also

likely result from a prenatal destructive lesion, probably

ischaemic. However, when they occur remains unclear as well

as whether these events occur simultaneously or separately.

In addition, unilateral cerebellar hypoplasia may be found as

an incidental asymptomatic finding during the assessment of

non-cerebellar disorders. For example, we found a hypoplasia

of the right cerebellar hemisphere in the investigation of

a 12 year old boy with headaches (Fig. 3). Unilateral cerebellar

hypoplasia has also been associated with some syndromes

such as Prader–Willi syndrome52 or Schimke immuno-

osseous dysplasia.53 In our view this finding is very likely to be

coincidental because children with a syndromic condition are

more often investigated with MRI.

Fig. 4 – Hypoplasia of the right cerebellar hemisphere

diagnosed at 20 weeks gestation: MRI confirming an

incidental finding on routine ultrasound (not shown).

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 3 9 7 – 4 0 7 401

3.3. Cerebellar agenesis

Complete (total) cerebellar agenesis is extremely rare and is

not compatible with life, as it has never been reported in living

subjects. In fact, therefore, the term ‘‘cerebellar agenesis’’ is

inappropriate. Hence we suggest that this designation should

only be used in patients with minute cerebellar tissue, usually

corresponding to remnants of the lower cerebellar peduncles,

anterior vermal lobules, and flocculi (Figs. 6 and 7).54 The

posterior fossa is of normal or increased size and contains the

brainstem, which always showed marked pontine hypoplasia,

and a collection of cerebrospinal fluid which passively fills the

space normally occupied by the cerebellum (Fig. 6). Only a few

such patients have been reported.54–58 All patients with iso-

lated, non-syndromic cerebellar agenesis have been sporadic

observations. It is only in rare instances that cerebellar

agenesis has been reported in the context of a complex

syndrome.56 The pathogenesis of cerebellar agenesis is not

definitively clear. We consider it to be a disruption and it is

conceivable that cerebellar agenesis represents the most

severe form of cerebellar disruption. Indeed, unilateral cere-

bellar aplasia may be the result of a unilateral disruptive

event, whereas a bilateral disruptive event could be consid-

ered as an explanation for cerebellar agenesis. All patients

with cerebellar agenesis were symptomatic.58–60 Children

surviving infancy had variable degrees of cerebellar dysfunc-

tion (truncal and limb ataxia, dysarthria) as well as cognitive

impairment.58,60 Only the woman reported by Sener and Jin-

kins appeared to be asymptomatic.61

We have seen two additional children with near complete

cerebellar agenesis (data not published) (Figs. 6 and 7). The

first patient was born at term by uncomplicated delivery

following an uneventful pregnancy. During the first year she

developed a tetraspastic cerebral palsy and a secondary

microcephaly. The MRI revealed extensive additional cerebral

white matter loss reminiscent of periventricular leukomala-

cia, which represents a clearly acquired, not hereditary lesion

(Fig. 6C). Therefore, we think that this imaging combination

corroborate our hypothesis, that cerebellar agenesis may be

acquired. The second child was examined at 12 months

because of developmental delay. MRI (Fig. 7) showed subtotal

cerebellar agenesis. In this patient as well as in case 3 pub-

lished by Gardner et al.,57 a foetal ultrasound had demon-

strated normal cerebellar anatomy at 18 and 22 gestational

weeks respectively. This fact also supports a disruption.

3.4. Unilateral cerebellar cleft

Cerebellar clefts are rare. For the first time, we have separately

reported six cases in detail.62 Cerebellar clefts principally

affect the cortical grey substance and extend from the hemi-

sphere’s surface into the parenchyma, reaching the fourth

ventricle in some cases but not involving the vermis (Fig. 8).

Malorientation of the cerebellar foliation, an irregular grey/

white matter junction, and lack of normal architecture of the

white matter have also been seen but only confined to the

region adjacent to the cleft. Due to the clefts and consequent

tissue loss, the affected cerebellar hemispheres were reduced

in volume, resulting in asymmetrically sized cerebellar

hemispheres. In two of six cases, cerebellar clefts were asso-

ciated with supratentorial clefts such as schizencephaly. In

two cases a foetal cerebellar haemorrhage could be detected

in the 24th week of gestation. Therefore we conclude that

cerebellar clefts represent a disruption resulting from

a prenatal haemorrhage. The clinical presentations were

highly variable, ranging from tetraparesis and cognitive and

speech impairment to almost normal development, and were

primarily related to the supratentorial abnormalities.

Fig. 5 – Hypoplasia of the left cerebellar hemisphere in

a 3 month old child with a lobar holoprosencephaly:

coronal T2-weighted MRI showing asymmetry of the

cerebellar hemispheres with hypoplasia of the left

cerebellar hemisphere and a complete lack of separation of

the cerebral hemispheres with a single midline forebrain

ventricle.

Fig. 7 – Cerebellar agenesis in a 1 year old child: sagittal T1-

weighted MRI revealing an enlarged fossa posterior,

marked hypoplasia of the pons, and almost complete

absence of cerebellar structures except for remnants

located in the anterior vermal area.

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3.5. Vanishing cerebellum in myelomeningocele

In myelomeningocele, prenatal hindbrain herniation through

the foramen magnum is a secondary result of prolonged

prenatal cerebrospinal fluid leak. This herniation may result

in parenchymal damage due to ischaemia, presumably

induced by mechanical distortion. When tissue loss is severe,

Fig. 6 – Cerebellar agenesis in a 15 year old child: (A) sagittal T2

the cerebellar structures are almost absent except for a rudime

and the pons is markedly hypoplastic; (B) axial T2-weighted MR

to the brainstem and an enlarged posterior fossa; (C) supratent

grossly reduced or virtually no cerebellum may be present, as

seen in a minority of patients (Fig. 9). This infrequent obser-

vation was called ‘‘vanishing cerebellum in Chiari II malfor-

mation’’ by Sener.63 However, this designation does not reflect

the remarkable asymmetry of tissue damage for which we

have no obvious explanation. The damage basically involves

one hemisphere, sparing the vermis. We reported three

patients with this phenomenon.64 In one patient, vanishing

cerebellum was already detectable at 25 weeks of gestation by

prenatal ultrasound and the tissue damage was remarkably

asymmetric in all patients. An appropriately tested child

showed severe cognitive impairments. However, the other

two patients could not be adequately assessed (one patient

-weighted MRI showing an empty enlarged posterior fossa;

ntary structure projecting posterior to the inferior colliculi,

I demonstrating minute cerebellar tissue projecting lateral

orial T2-weighted MRI revealing loss of the white matter.

Fig. 8 – Cerebellar cleft in a 1.5 year old child: (A) coronal

T2-weighted MRI revealing a left paravermian cleft

extending to the lateral recess of the fourth ventricle;

(B) axial T2-weighted MRI showing a left-sided cleft,

malorientation of the adjacent cerebellar folia, and

abnormal arborisation of the white matter.

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died early and another was still too young for final assess-

ment). Therefore no conclusion on the cognitive consequence

of vanishing cerebellum can be drawn from the available

literature. However, we hypothesise that vanishing cere-

bellum impairs cognitive development.64

3.6. Disruption of cerebellar development inpreterm infants

Several follow-up studies in very low birth weight premature

(VLBWP) infants have revealed a significant number of cere-

bellar defects.65–67 Most affected children are born before

28 weeks but it can also be found in neonates born before

32 weeks of gestation and all have a very low birth weight (less

than 1500 g).66 The cerebellar hemispheres are predominantly

affected, the vermis is small and its shape variably preserved,

the fourth ventricle is of variable size, and the brain stem is

small with a flattened pons (Fig. 10). Therefore Messerschmidt

et al. recognised three different morphological patterns: (1)

symmetrical volume reduction of the cerebellar hemispheres,

which were ‘‘floating’’ immediately beneath the tentorium,

and a small vermis with preserved shape; (2) symmetrical

reduction in hemispheric volume with an enlarged, balloon-

shaped fourth ventricle and a small, deformed vermis; and (3)

normal overall cerebellar shape with extensive reduction of its

dimensions.66

Messerschmidt et al. reported normal cerebellar ultra-

sound scans in the first few days of life, confirming that the

lesions were acquired.68 Because similar cerebellar patholo-

gies are not observed in children born after the 32nd gesta-

tional week, the disruption may be related to cerebellar

developmental steps at 24–32 gestational weeks.

Cerebellar tissue loss seems to be of great functional

importance. Indeed, VLBWP with cerebellar lesions all had

mental retardation, and epilepsy and microcephaly were also

common findings.65,69 Even in less extensively expressed

cerebellar lesions, a significant association was found

between neuropsychological dysfunction and volume decre-

ment of the lateral cerebellar lobes in adolescents who were

born very prematurely.70,71

4. Discussion

The spectrum illustrated demonstrates the importance of

cerebellar imaging as a clue to a wide range not only of mal-

formations, but also of disruptions. Disruptive mechanisms

can affect the cerebrum and/or the cerebellum. However,

cerebrum and cerebellum are variably vulnerable to the

different disruptive factors in the prenatal period. On the basis

of the disorders described, it appears that in the prenatal

period the cerebellum is particularly vulnerable to infections

and haemorrhages, as summarised in a simplified manner in

Table 1.72 Perinatally, the cerebellum is vulnerable in

extremely preterm babies, whereas metabolic and toxic

insults particularly affect the cerebellum in the postnatal

period. However, the cerebellum is mostly resistant to

prenatal, perinatal and postnatal hypoxic-ischaemic

events15,72,73 and the reports about cerebellar involvement in

perinatal hypoxia in neonates at term are few.74,75 Therefore,

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besides prematurity, prenatal cerebellar disruptions, infec-

tions and haemorrhages are the most important factors

affecting the developing cerebellum.

Congenital CMV infection is a leading cause of intrauterine

infection and has been associated with cerebellar hypo-

plasia.31,32,76 CMV can also affect neuronal migration such as

lissencephaly or polymicrogyria. It appears that neuronal

migration disorders in congenital CMV infection originate

from the disturbance of cellular processes within the

ventricular zone in which stem cells are proliferating, as well

as from disruption of the movement of these cells away from

the ventricular zone.77 The association between cerebellar

hypoplasia and lissencephaly has also been reported in

hereditary migration disorders, particularly due to mutations

in the reelin gene (RELN) on chromosome 7q22.23,24 Miyata

et al. reported that the external granular layer of the cere-

bellum was hypoplastic in a patient with a mutation in the

RELN gene.24 This may be due to an abnormal migration of the

stem cells from the lateral rhombic lips, forming the external

granular layer.78 Therefore, it seems likely that cerebellar

hypoplasia is also a consequence of impaired migration. This

process begins at 12 weeks and lasts until about 16 weeks of

gestational age. Furthermore, it is known that in the presence

of lissencephaly the infection seems to occur before 16–

18 weeks.32 Therefore, it is possible that a congenital CMV

infection causing a cerebellar hypoplasia occurs between 12

and 16 weeks gestation.

Prenatal cerebellar haemorrhages and also disrupted

cerebellar development in preterm infants originate later in

gestation. Prenatal cerebellar haemorrhages have been

increasingly reported in the literature.37–44 In these reports the

cerebellar haemorrhages were detected between 21 and

24 weeks gestation. Around 24 weeks gestation, the cere-

bellum seems to be particularly vulnerable. Indeed, cerebellar

haemorrhages occur within the germinal zone located in the

subpial external granule cell layer, which is thickest at

24 weeks gestation and begins to involute at 30 weeks gesta-

tion.79,80 Subpial germinal matrix bleeding can then cause

intrahemispheric cerebellar haemorrhages, as described in

the literature.80

Disrupted cerebellar development in preterm infants is

only observed in those born before the 32nd gestational

week, typically before 28 weeks gestation. Because the

cerebellum is highly vulnerable in the period between 24

and 30 weeks of gestation, the disruption may be related to

these developmental steps.66,78 However, the exact patho-

mechanism of the disruption of cerebellar development in

VLBWP has not been definitively explained. Direct cere-

bellar injuries such as haemorrhage or infarction seem

improbable. Indeed, in several patients Messerschmidt

et al. were able to document a continuous decline of

Fig. 9 – Vanishing cerebellum in a 5 month old child with

myelomeningocele: (A) sagittal T2-weighted MRI

demonstrating a very small posterior fossa and a lack of

pontine prominence; (B) coronal T2-weighted MRI showing

marked destruction of the right cerebellar hemisphere

(reproduced from Boltshauser E et al., Eur J Paediatr Neurol,

2002, with permission).

Table 1 – Cerebellar vulnerability.

Conditions Cerebellarvulnerability

Selectedreferences

Hypoxic-ischaemic events including

perinatal asphyxia at term

(þ) 74,75

Postnatal infections þ 73

Prematurity (<30 weeks GA) þ 65,66

Prenatal infections

(in particular CMV)

þþ 31,32

Prenatal haemorrhages þþþ 80

Toxicity/selected drugs þþþ 73

Metabolic disorders þþþþ 15,73

CMV, cytomegalovirus; GA, gestational age.

Fig. 10 – Disrupted cerebellar development in a 1.6 year old

child born preterm at 27 weeks gestation and suffering

from posthaemorrhagic hydrocephalus: (A) sagittal

T2-weighted MRI showing a longitudinal and small vermis

and enlarged third and fourth ventricle; (B) coronal

T2-weighted MRI revealing small, asymmetric cerebellar

hemispheres located laterally in the posterior fossa and

enlarged third and lateral ventricles.

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 3 9 7 – 4 0 7 405

cerebellar volume over several weeks without any typical

vascular injury pattern. A correlation between associated

brain injury such as intraventricular haemorrhages and the

severity of cerebellar volume decline in premature infants

has been described.81,82 However, this cannot be the only

pathomechanism, since other reports failed to show this

correlation.66 Messerschmidt et al. reported that superficial

haemosiderin deposition on the cerebellar surface was the

most important risk factor for disruption of cerebellar

development and may be the pathway to cell death and

olivopontocerebellar degeneration.68

We are well aware of a general limitation of this

manuscript as we describe ‘‘macroscopic’’ lesions detect-

able with present routine neuroimaging techniques. Subtle

‘‘microscopic’’ alterations such as chronic intrauterine

hypoxic-ischaemia are below the present limits of resolu-

tion of MRI.

5. Conclusion

Cerebellar disruptions appear to be common, potentially

mimicking cerebellar malformations, although the patho-

genesis is completely different. Cerebellar disruptions pre-

senting different morphological patterns can be caused by

the same disruptive agent, such as a cerebellar haemor-

rhage. This fact reveals that the different disruption

patterns are not several independent disorders, but are

likely to represent a morphological spectrum of the same

pathogenetic mechanism. Therefore, a clear classification

of these patterns remains difficult to achieve. It is to be

expected that at least part of the present uncertainty will

be resolved by progress in the understanding of cerebellar

embryology and the pathogenetic mechanisms of the

different disruptive agents. Pooling of data on cerebellar

disruptions and their evaluation by expert working groups,

as well as animal studies, may prove successful. Without

doubt, the recognition of cerebellar disruptions and their

differentiation from cerebellar malformations are impor-

tant in terms of diagnosis, prognosis, and genetic

counselling.

Acknowledgements

Dr. Poretti was financially supported by a donation from the

United Bank of Switzerland (UBS). This donation was made at

the request of an anonymous client.

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 3 ( 2 0 0 9 ) 3 9 7 – 4 0 7406

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