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Differential Diagnosis of Cerebellar Atrophy in Childhood: An Update

Article  in  Neuropediatrics · October 2015

DOI: 10.1055/s-0035-1564620

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 Review Article

Differential Diagnosis of Cerebellar Atrophy in

Childhood: An Update
Andrea Poretti1,2 Nicole I. Wolf3 Eugen Boltshauser1

1 Department of Pediatric Neurology, University Children’s Hospital of
Zurich, Switzerland
2 Section of Pediatric Neuroradiology, Division of Pediatric Radiology,
Russell H. Morgan Department of Radiology and Radiological
Science, The Johns Hopkins University School of Medicine, Baltimore,
Maryland, United States
3 Department of Child Neurology, VU University Medical Center and
Neuroscience Campus, Amsterdam, The Netherlands
Address for correspondence Andrea Poretti, MD, Section of Pediatric
Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan
Department of Radiology and Radiological Science, The Johns Hopkins
University School of Medicine, Zayed Building Room 4174, 1800
Orleans Street, Baltimore, MD 21287, United States
(e-mail: aporett1@jhmi.edu).

Neuropediatrics

Abstract Cerebellar atrophy (CA) is a relatively common, but nonspecific finding in pediatric
neurology and neuroradiology. Here, we provide an update of checklists for postnatally
acquired CA, unilateral CA, and hereditary CA. In addition, we include a list of disorders
with ataxia as a symptom, but without CA. These checklists may help the evaluation of
differential diagnosis and planning of additional investigations. For diseases associated
with hereditary CA, we provide an updated version of our neuroimaging-based pattern-
Keywords recognition approach that classify CA as isolated (“pure”) or associated (“plus”) with
► cerebellum other neuroimaging findings including hypomyelination, progressive white matter
► cerebellar atrophy abnormalities, signal changes of the dentate nucleus, cerebellar cortex T2-hyperinten-
► children sity, and basal ganglia involvement. Finally, we discuss some rules with their exceptions
► neuroimaging related to pediatric CA, discrepancies between clinical and neuroimaging course, and
► pattern-recognition the difficulties to differentiate CA from cerebellar hypoplasia.

Introduction differentiated between isolated CA and CA associated with

Cerebellar atrophy (CA) is a relatively common finding in
pediatric neurology and neuroradiology. CA is defined as a
cerebellum with initially normal structures, in a posterior
fossa with normal size, which displays enlarged fissures
(interfolial spaces) in comparison to the foliae secondary to
tissue loss.1 CA implies irreversible loss of tissue and is
assumed to result from an ongoing progressive disease until
a final stage is reached or from a single injury, for example, an
intoxication or infectious event.
CA is a nonspecific neuroimaging finding and has been
associated with a long list of pediatric diseases including
genetic and acquired causes. In 2008, we proposed a pattern-
recognition approach for hereditary pediatric CA.1 We
additional neuroimaging findings such as hypomyelination,
progressive white matter abnormalities, basal ganglia in-
volvement, and cerebellar white matter changes. This pat-
tern-recognition approach has been used in subsequent
studies of CA.2–4
Since 2008, given the incredible advances in sequencing
techniques and the increasing application of whole exome
sequencing to study cohorts of children with neurological
diseases, a considerable number of diseases associated with
CA have been reported. We decided to update our 2008
pattern-recognition approach of pediatric CA including new
disorders associated with CA. In addition, we will discuss
some general rules as well as some aspects related to the
clinical and neuroimaging course of children with CA.

received © 2015 Georg Thieme Verlag KG DOI http://dx.doi.org/

June 16, 2015 Stuttgart · New York 10.1055/s-0035-1564620.
accepted after revision ISSN 0174-304X.
August 12, 2015
Cerebellar Atrophy in Children: An Update Poretti et al.

Disease Selection patients.3 The authors found that mitochondrial disorders

The conditions listed in ►Tables 1–4 and ►Table 1, Supple-
mentary Material (available in the online version only) have
been selected from the following sources: for many years, we
have been collecting patients with CA in our clinical practice
and from consultations for “second opinions.” We consulted
textbooks on cerebellar disorders, ataxia disorders, and
neuroimaging. We collected literature reports with regard
to cerebellar involvement. PubMed was searched with appro-
priate keywords.
This approach is related to potential problems and limi-
tations: (1) CA may be only a late finding in some diseases, (2)
CA may be mentioned in single cases, which do not necessar-
ily reflect the classic neuroimaging presentation of a particu-
lar disease, (3) CA is reported in the text, but is not illustrated
or only poorly described, and (4) in selected disorders such as
Cayman island ataxia and Marinesco–Sjögren syndrome,
some references use the term CA to describe the neuroimag-
ing findings, while other articles prefer the term “cerebellar
hypoplasia” (CH). Therefore, the updated checklists do not
aim to be lexical and complete, but they represent an updated
“work in progress” that will require further updates in the
future.
The design of this article does not allow to evaluate the
prevalence of the various diseases that are associated with CA.
Al-Maawali et al from The Hospital for Sick Children in
Toronto reviewed data of 300 children with hereditary CA
and were able to make a final diagnosis in 47% of the
were the most common, followed by neuronal ceroid lip-
ofuscinosis, ataxia telangiectasia, and late-onset GM2 gan-
gliosidosis. The relative prevalence, however, may vary
between different institutions due to different ethnicity,
potential service to inbred populations, referral bias, and
other factors.
Checklists and Pattern-Recognition
Approach
We arbitrarily classified the diseases associated with CA into
following groups: (1) hereditary CA due to metabolic or other
genetic causes (►Table 1, Supplementary Material available
in the online version only), (2) acquired CA due to pre- and
postnatal disorders (►Table 1, ►Figs. 1 and 3, Supplemen-
tary Material available in the online version only) unilateral
CA due to pre- and postnatal diseases (►Table 2, ►Fig. 2,
Supplementary Material available in the online version
only). In addition, we included a list of diseases with cere-
bellar ataxia without CA (►Table 3). The most important
clinical and additional neuroimaging findings as well as
relevant comments, OMIM numbers (if pertinent), and se-
lected references are also included, to facilitate differential
diagnosis. For the table on hereditary CA, we added the
involved gene(s), time of clinical onset, onset of CA compared
with clinical onset, and the degree of CA.
The first step of the neuroimaging based pattern-recognition
approach of pediatric hereditary CA (►Table 4) includes the

Table 1 Acquired CA in childhood

Condition Comments Selected

reference
16
Extreme prematurity Risk factors: GA < 30 wks, IVH
52
Neonatal hypoxic-ischemic encephalopathy Full term, superior vermis atrophy
53
Post “inflammatory” (¼ post “cerebellitis”) Exceptional observations, often clinically “silent”
54
Multiple sclerosis Brainstem also affected
55
Posttraumatic brain injury Moderate-to-severe trauma, global atrophy
56
Paraneoplastic Hodgkin disease Rare, diffuse CA
57
Langerhans cell histiocytosis Global atrophy
58
OMS CA as late sequelae
59
Chronic epilepsy Not due to AED intoxication
Radiation therapy CA as early sequelae Own experience
Posterior fossa surgery CA as late sequelae Own experience
60
Malnutrition Vitamin B12 deficiency Related to breastfeeding in vegan mothers,
cerebral > cerebellar atrophy
61
Toxic Phenytoin and other AED Children, adolescents
62
Tacrolimus Children, adolescents
60
Incidental intoxication Children, adolescents
60,63
Alcohol, solvents, heavy metals, drugs Adolescents

Abbreviations: AED, antiepileptic drugs; CA, cerebellar atrophy; GA, gestational age; IVH, intraventricular hemorrhage; OMS, opsoclonus myoclonus
syndrome.

Neuropediatrics
 Cerebellar Atrophy in Children: An Update Poretti et al.

Fig. 1 Pure cerebellar atrophy (CA). (A) Axial T2- and (B) midsagittal T1-weighted images of an 8-year-old child with ataxia telangiectasia show
pure moderate CA with predominant involvement of the superior vermis and secondary enlargement of the fourth ventricle (Reprinted with
permission from Poretti et al 1). (C) Axial T1- and (D) midsagittal T2-weighted images of a 5-year-old child with ataxia ocular motor apraxia type 1
reveal pure moderate CA with secondary enlargement of the fourth ventricle. (E) Axial T2- and (F) midsagittal T1-weighted images of an 2-year-old
child with autosomal recessive spinocerebellar ataxia type 14 and homozygous mutations within the SPTBN2 gene show mild pure CA. (G) Axial T2-
and (H) midsagittal T1-weighted images of an 6-year-old male with coenzyme Q10 deficiency and compound heterozygous mutations within the
ADCK3 gene reveal moderate pure CA with secondary enlargement of the fourth ventricle. (I) Coronal and (J) midsagittal T1-weighted images of a
2-year-old child with mutation within the ITPR1 gene show moderate pure CA with secondary enlargement of the fourth ventricle.

differentiation between isolated CA (“pure CA,” ►Fig. 1) and CA
associated with other cerebellar or supratentorial neuroimaging
findings (“CA plus”). Additional neuroimaging findings that we
considered for the pattern-recognition approach include: (1)
hypomyelination (►Fig. 3, Supplementary Material available in
the online version only), (2) progressive white matter abnor-
malities (►Fig. 4, Supplementary Material available in the
online version only), (3) signal change of the dentate nucleus,
(4) cerebellar cortex T2-hyperintensity (►Fig. 2), and (5) basal
ganglia involvement (►Fig. 5, Supplementary Material avail-
able in the online version only). Progressive white matter
abnormalities have been further classified based on the location
(e.g., frontal, periventricular, occipital, cerebellar, brainstem, and
subcortical predominance or diffuse involvement). Basal ganglia
involvement has been subdivided based on the presence of (1)
calcifications, (2) atrophy, and (3) signal changes.
Neuroimaging in Pediatric Cerebellar
Atrophy
Conventional magnetic resonance imaging (MRI) allows a de-
tailed evaluation of the anatomy of the posterior fossa and its
contents.5,6 A midline sagittal T1- or T2-weighted sequence is
ideal to show the size of the posterior fossa, vermis, fourth
ventricle, supravermian cistern, and brainstem. In CA, the fourth
ventricle and supravermian cistern are secondarily enlarged. On
parasagittal images, the cerebellar hemispheres and peduncles
can be assessed. On axial images, the size, morphology, and
signal of the vermis, cerebellar hemispheres, cerebellar white
matter, and dentate nuclei are evaluated. On axial images,
enlarged interfolial spaces of both vermis and hemispheres are
usually best seen in the uppermost and lowest sections. In
addition, axial images are essential for assessment of the

Table 2 Unilateral CA in childhood

Condition Comments Selected

reference
64
Unilateral cerebellitis Cerebellitis has usually bilateral involvement, rare unilateral
65
Unilateral ischemic infarction Rarely isolated, different etiologies: embolic, traumatic
Unilateral traumatic brain injury/concussion Own experience
Following posterior fossa surgery Unilateral CA as late sequelae Own experience
66
Crossed cerebro cerebellar diaschisis Unilateral cerebellar atrophy contralateral to a
supratentorial lesion of different etiology
67
Unexplained origin

Abbreviation: CA, cerebellar atrophy.

Neuropediatrics
Cerebellar Atrophy in Children: An Update Poretti et al.

Fig. 2 Cerebellar atrophy (CA) and cerebellar cortex T2-hyperintensity. (A) Sagittal T1-weighted, (B) axial fluid attenuation inversion recovery
(FLAIR), and (C) axial T2-weighted images of a 6-year-old child with infantile neuroaxonal dystrophy show moderate CA with secondary
enlargement of the fourth ventricle, FLAIR-hyperintense signal of the cerebellar cortex, and T2-hypointense signal of the globi pallidi (Reprinted
with permission from Poretti et al 1). (D) Sagittal T1-weighted, (E) axial FLAIR, and (F) axial T2-weighted images of a 9-year-old boy with
Christianson syndrome reveal moderate CA with secondary enlargement of the fourth ventricle and diffuse FLAIR-hyperintense signal of the
cerebellar cortex (Reprinted with permission from Bosemani et al 9).

supratentorial structures of interest, especially white matter
(e.g., hypomyelination or progressive white matter signal abnor-
malities), cortex (e.g., atrophy), and basal ganglia (e.g., calcifica-
tions, atrophy, and/or signal changes). The coronal images are
particularly informative: they provide an excellent overview of
both vermis and hemispheres (e.g., predilection of involvement,
enlargement of the interfolial spaces, and/or signal changes of
cerebellar white matter and cortex). Fluid attenuation inversion
recovery (FLAIR) images are important to show signal changes of
the cerebellar cortex (e.g., in infantile neuroaxonal dystrophy
and Christianson syndrome), which can be misinterpreted on
T2-weighted images due to the hyperintense cerebrospinal fluid
(CSF) surrounding the atrophic cerebellar cortex. Hyperintense
signal of the cerebellar cortex is best seen on coronal images.
FLAIR images, however, can falsely minimize the degree of CA.
Advanced neuroimaging techniques may be helpful depend-
ing on the clinical presentation, suspected diagnosis, or encoun-
tered pathology.7 Diffusion weighted imaging (DWI) and
diffusion tensor imaging (DTI) is helpful to differentiate vaso-
genic, interstitial, cytotoxic, or so-called myelin (intramyelinic)
edema. DWI and DTI play an important role in the acute workup
of metabolic diseases associated with CA and contribute to
elucidate the pathomechanism of CA in some disorders.7,8
Finally, DWI and DTI provide detailed qualitative and quantita-
tive information about the white matter microstructure that
may be used as longitudinal biomarkers to follow the course of
the disease and/or monitor the effect of treatment. Susceptibili-
ty-weighted imaging is highly sensitive for blood, blood prod-
ucts, and calcifications and may be helpful in demonstrating
calcifications and brain iron accumulation in diseases associated
with CA.1,9 H-MR spectroscopy provides information about
several brain metabolites and may be helpful in the acute
workup of selected metabolic diseases associated with CA
(e.g., mitochondrial disorders). In addition, 1H-MR spectroscopy
can monitor temporal changes in cerebellar neurometabolites in
the natural course of a disease as well as under therapy.7,8 In CA,
voxel placing may be challenging and contamination with CSF
should be avoided.
Involvement of the Cerebellar Vermis and
Hemispheres
CA is typically more pronounced in the cerebellar vermis
compared with the hemispheres, but atrophy may globally
involve the entire cerebellum to a similar degree. There are
only few exceptions to this rule (►Fig. 3).
In some forms of pontocerebellar hypoplasia (PCH as
conceptualized by Peter Barth as neurodegenerative disor-
ders with prenatal onset), a “dragonfly” appearance on
coronal images is the characteristic finding: flattened cere-
bellar hemispheres represent “the wings,” while the relatively
preserved vermis represents “the body.”10 The dragonfly
appearance is typically seen in PCH type 2 due to homozygous
p.A307S mutations in TSEN54. A “dragonfly” appearance may

Neuropediatrics
 Cerebellar Atrophy in Children: An Update Poretti et al.

Table 3 Diseases with ataxia without CA in childhood

Disease OMIM Comments Selected

reference
26
Nonprogressive cerebellar ataxia AT, MR, speech impairment
68
Friedreich ataxia 229300 Cervical cord atrophy, AT, peripheral sensory NP,
hypertrophic cardiomyopathy
69
Vitamin E deficiency 277460 Low-serum vitamin E, areflexia, spinocerebellar AT,
proprioception loss
70
Refsum disease 266500 Elevated serum phytanic acid, RP, AT, NP, hearing impairment
71
Abetalipoproteinemia 200100 Very low serum cholesterol, diarrhea, akanthocytosis, AT, NP
72
Glucose transporter 1 deficiency 606777 Hypoglycorrhachia, acquired micro, infantile epi,
delayed development
73
Cogan 257550 Ocular motor apraxia, AT, MR (inconsistent)
74
Angelman syndrome 105830 MR, AT, abnormal behavior, severe limitations in
speech and language
75
Rett syndrome 312750 Dementia, autism, hands stereotypies, AT, acquired micro

Abbreviations: AT, ataxia; micro, microcephaly; MR, mental retardation; NP, neuropathy; RP, retinitis pigmentosa.
Note: Wide-base gait has been reported also in following disorders that are not associated with cerebellar atrophy: Mowat–Wilson syndrome, Pitt–
Hopkins syndrome, Prader–Willi syndrome, Chromosome 2q23.1 deletion syndrome, Phelan–McDermoid syndrome, MECP2 duplication syndrome,
and methylene tetrahydrofolate reductase deficiency.76

be also seen in patients with PCH type 2 and other TSEN54
missense mutations as well as TSEN2 and TSEN34 mutations,
and in some patients with PCH type 1 and PCH type 4.11,12 In
other types of PCH, involvement of the cerebellar vermis and
hemispheres is similar resulting in a “butterfly” appear-
ance10–13 or, rarely, the cerebellar vermis is more affected
compared with the hemispheres as in PCH type 5.11,14,15
Predominant involvement of the cerebellar hemispheres
compared with the vermis has been also reported in very
low-birth-weight (less than 1,500 g) premature infants born
before 32 weeks of gestation.16,17 The cerebellar hemispheres
are markedly reduced in volume due to extensive loss of
white matter, and are positioned superiorly in the posterior
fossa, immediately beneath the tentorium. The vermis is
usually small, but its shape is variably preserved.
A “dragonfly” appearance has also been reported in some
patients with CASK mutation.18
In Unverricht–Lundborg disease, a form of progressive
myoclonus epilepsy, the vermis is not significantly atrophic,
whereas both cerebellar hemispheres show loss of bulk.19
Brainstem Involvement
The vast majority of hereditary CA does not lead to significant
reduction in volume of the brainstem, particularly of the pons,
even in advanced stage. Some degree of pontine atrophy may be
seen in later stages of spinocerebellar ataxias (SCA) with pediat-
ric onset, such as SCA2 or SCA7,20,21 Wolfram syndrome,22 and
Boucher–Neuhäuser syndrome.23
Other exceptions of this rule include diseases with prenatal
loss of cerebellar tissue: (1) hereditary disorders with prenatal
onset CA including the group of PCH as prenatal onset neurode-
generative disorders10 and congenital disorder of glycosylation
type 1a due to PMM2 mutations,24 as well as (2) acquired
disorders with prenatal onset cerebellar disruptive lesions
such as cerebellar agenesis and vanishing cerebellum in myelo-
meningocele,25,26 and anencephaly (►Fig. 4).27 In addition,
marked reduction in size of the pons has been shown in very
low-birth-weight (less than 1,500 g) premature infants born
before 32 weeks of gestation.16,17
These observations suggest that the pontine prominence
seems to be present only if a significant part of cerebellum
has been developed. This may be explained by the fact that the
ventral prominence of the pons consists of transverse fibers
arched like a bridge across the median plane converging along
each side into a compact mass, which forms the middle cerebel-
lar peduncles. The middle cerebellar peduncles are the most
important afferent pathway to the cerebellum. A prenatal
absence or loss of cerebellar tissue most likely results in a
retrograde axonal degeneration of the middle cerebellar pe-
duncles and hence a reduction in pontine prominence.
T2-Hyperintense Signal of the Cerebellar
Cortex
Hyperintense signal of the cerebellar cortex on T2-weighted
images has been considered a rare neuroimaging finding that is
pathognomonic for infantile neuroaxonal dystrophy.28–31 In the
meantime, however, T2-hyperintense signal of the cerebellar
cortex has been reported in a variety of additional diseases
associated with CA including Marinesco–Sjögren syndrome,32
congenital disorders of glycosylation type 1A due to PMM2
mutations,24 mitochondrial disorders such as complex I defi-
ciency due to NUBPL mutations33,34 and coenzyme Q10 defi-
ciency,35 Christianson syndrome,36 pontocerebellar hypoplasia
type 7, advanced-stage late-onset GM2 gangliosidosis,3 SCA,3
and late infantile neuronal ceroid lipofuscinosis (►Fig. 2). In
addition, we have seen T2-hyperintense signal of the cerebellar

Neuropediatrics
Cerebellar Atrophy in Children: An Update Poretti et al.

Table 4 Pattern-recognition approach of pediatric CA

Pattern
Pure CA
CA and hypomyelination
CA and progressive white matter
abnormalities (predominance)a
CA and signal change of the
dentate nucleus
CA and cerebellar cortex
T2-hyperintensity
CA and basal ganglia involvement
Disease
Ataxia telangiectasia; ataxia telangiectasia like disorder;
late-onset GM2 gangliosidosis; ataxia-oculomotor apraxia
type 1 and type 2; PEHO syndrome; CACNA1A-mutation
(including episodic ataxia type 2; SCA6; familial
hemiplegic migraine type 1); mevalonate kinase deficiency;
SCAR7 (TPP1 gene); SCAR10 (ANO10 gene); SCAR13
(GRM1 gene); SCAR14 (SPTBN2 gene); SCA29 (ITPR1 gene);
predominant dystonia with CA; GRID2 mutation; coenzyme
Q10 deficiency; some mitochondrial disorders
Pelizaeus–Merzbacher disease; Pelizaeus–Merzbacher
like disease; Salla disease; 4H; H-ABC; galactosemia;
trichothiodystrophy
Frontal predominance Infantile neuroaxonal dystrophy
Periventricular Neuronal ceroid lipofuscinoses (particularly
late-infantile type); Niemann–Pick disease type C;
adenylosuccinase deficiency
Occipital predominance Early-onset peroxisomal disorders
Subcortical L-2-hydroxyglutaric aciduria; Kearns–Sayre syndrome
Diffuse cerebral Vanishing white matter disease; some mitochondrial disorders
Cerebellar Peroxisomal disorders; cerebrotendinous xanthomatosis
Brainstem Wilson disease; peroxisomal disorders; Leigh syndrome;
dentato-rubral-pallido-luysian atrophy
Multifocal Some mitochondrial disorders; galactosemia; infantile
neuroaxonal dystrophy; L-2-hydroxyglutaric aciduria
L-2-hydroxyglutaric aciduria; cerebrotendinous
xanthomatosis; Wilson disease; Succinic semialdehyde
dehydrogenase deficiency
Infantile neuroaxonal dystrophy; Marinesco–Sjögren syndrome;
congenital disorders of glycosylation 1a; Christianson
syndrome; coenzyme Q10 deficiency; late infantile neuronal
ceroid lipofuscinosis; pontocerebellar hypoplasia type 7; some
forms of nonprogressive cerebellar ataxia; some mitochondrial
disorders
Calcifications Kearns–Sayre syndrome; other mitochondrial disorders;
Cockayne syndrome; Aicardi–Goutières syndrome; MELAS
Atrophy H-ABC; Wilson disease (late); Huntington chorea (inconsistent)
Signal changes Mitochondrial disorders; Wilson disease; 3-methylglutaconic
aciduria

Abbreviations: CA, cerebellar atrophy; H-ABC, hypomyelination with atrophy of the basal ganglia and cerebellum.
a
Progressive white matter involvement was classified based on the anatomical location, not based on the underlying pathomechanism (primary and
secondary white matter abnormalities are included in the same groups).

cortex in several children with nonprogressive cerebellar ataxia
and stable enlargement of the cerebellar foliae mimicking CA.
In some diseases with CA and T2-hyperintense signal
of the cerebellar cortex, histopathology showed severe
loss of Purkinje cells and reactive proliferation of micro-
glial cells such as Bergmann glia. 37–39 On T2-weighted
imaging, gliosis is characterized by T2-hyperintense
signal. The proliferation of microglial cells within the
cerebellar cortex may represent the underlying biologi-
cal pathomechanism of T2-hyperintense signal of the
cerebellar cortex in CA.
Although this neuroimaging finding is called “T2-hyperin-
tense” signal of the cerebellar cortex, it is best seen on FLAIR
images, particularly coronal images. The contrast between the
hypointense CSF and the hyperintense cerebellar cortex is best
demonstrated using FLAIR images.
The T2-hyperintense signal of the cerebellar cortex is incon-
sistent in several diseases (e.g., infantile neuroaxonal dystrophy
and Christianson syndrome).36,40 The inconsistent presence and
increasing number of associated diseases makes the T2-hyper-
intense signal of the cerebellar cortex less helpful in the clinical
routine.

Neuropediatrics
 Cerebellar Atrophy in Children: An Update Poretti et al.

Fig. 3 Three examples for more prominent atrophy of the cerebellar hemispheres compared with the vermis: Coronal T2-weighted images of (A) a
2-year-old child with pontocerebellar hypoplasia type 2 due to TSEN54 mutations, (B) ex preterm born at 32 weeks of gestation, and (C) a child with
CASK mutation. More pronounced atrophy of the cerebellar hemispheres compared with the vermis results in a dragonfly appearance.

Discrepancies between Clinical and In some diseases, CA has an early-onset and rapid initial
Neuroimaging Course progression followed by stable situation over a long period
despite clinical progression. This kind of CA dynamic has been
In the majority of diseases, the course of CA is progressive reported in ataxia-oculomotor apraxia type 2 and coenzyme
over time and goes along a progressive clinical course. There Q10 deficiency due to ADCK3 mutations or autosomal
are however exceptions to this rule. recessive cerebellar ataxia 2 (ARCA2).35,41 CA is an early

Fig. 4 Pontine involvement. (A) Sagittal T1-weighted image of a 2-year-old child with pontocerebellar hypoplasia type 2 and TSEN54 mutations
shows a mild reduction in size of the pons and mild hypoplasia of the cerebellar vermis. (B) Sagittal T2-weighted image of 15-old-girl with
cerebellar agenesis reveals marked reduction in size of the pons, almost complete absence of the cerebellum (only a rudimentary structure
projecting posterior to the inferior colliculi is present), and a prominent posterior fossa (Reprinted with permission from Poretti et al26). (C)
Sagittal T1-weighted image of a child with Chiari 2 malformation and vanishing cerebellum shows almost complete absence of the pontine
prominence. In addition, classic stigmata of Chiari 2 malformation are noted including a small posterior fossa, cerebellar herniation through the
foramen magnum, beaking of the tectal plate, prominent massa intermedia, and dysgenesis of the corpus callosum. (D) Sagittal T1-weighted
image of a 2-year-old child who was born at 29 weeks of gestation reveals a marked reduction in size of the pons, a small cerebellar vermis, a normal
configuration of the fourth ventricle, and a highly abnormal corpus callosum.

Neuropediatrics
Cerebellar Atrophy in Children: An Update Poretti et al.

Fig. 5 Discrepancy between clinical and neuroimaging course. (A) Sagittal and (B) axial T2-weighted images of a 4-year-old girl who was born at
30 weeks of gestation and presented with nonprogressive cerebellar ataxia, global developmental delay, and ocular motor apraxia shows a marked
enlargement of the interfolial spaces involving mostly the superior vermis. (C) Sagittal and (D) axial T2-weighted images of the same girl at
13 years of age reveals a mild progressive cerebellar atrophy, despite marked improvement in several developmental domains.

finding in these diseases and stabilizes after several years of
disease course. Another possible explanation for such a
dynamic is a very slowly progressive CA that needs long-
term follow-up studies to reveal imaging progression, while
MRI follow-up studies in children are usually performed in
short-term intervals. Alternatively, CA may have occurred
prenatally or before the first neuroimaging study (e.g., in CA
caused by intoxication or irradiation) and we see only the
final static phase.
A stable clinical course despite a mild progression of CA
has been reported in few articles. Huang et al reported on
two families with autosomal dominant nonprogressive
cerebellar ataxia caused by missense mutations in
ITPR1.42 CA has been identified as early as at 28 months
of age and was progressive on follow-up. Thevenon et al
described two families with autosomal dominant nonpro-
gressive cerebellar ataxia with or without intellectual
disability due to intragenic CAMTA1 rearrangement.43
Brain MRI revealed progressive CA that involved particu-
larly the medium lobes and superior vermis as well as
progressive atrophy of the parietal lobes and hippocampi.
Bertini et al reported one family with two males affected by
X-linked nonprogressive cerebellar ataxia, severe hypoto-
nia, and ocular movements abnormalities due to ATP2B3
mutations.44,45 In these patients, follow-up neuroimaging
studies showed global CA that was not evident in the first
years of life. We saw a 4-year-old girl who was born at
30 weeks of gestation and presented with nonprogressive
cerebellar ataxia, global developmental delay, and ocular
motor apraxia. A brain MRI at the age of 4 years showed a
marked enlargement of the interfolial spaces involving
mostly the superior vermis (►Fig. 5A, B). A clinical fol-
low-up at the age of 13 years showed marked improvement
in several developmental domains, while a neuroimaging
follow-up showed mild progression of CA (►Fig. 5C, D).
Improvement in motor performance has been shown in
adults with degenerative cerebellar disorders after coordi-
native training.46,47 Possible pathophysiological explana-
tion include the ability of the degenerating cerebellum to
adapt motor coordination and compensation of the learn-
ing deficit by other brain structures. In addition, we have to
consider the possibility that the disease may be slowly
progressive and clinical progression may be noted only
with long-term follow-up examinations.

Neuropediatrics

Recently, we investigated two siblings with pure pro-
gressive cerebellar ataxia and an opposite discrepancy
between clinical and neuroimaging course. The older
brother presented with severe clinical features (almost
loss of ambulation), and neuroimaging showed marked
global CA (►Fig. 6A–C). Surprisingly, neuroimaging showed
similar findings in the younger brother who was almost
asymptomatic at the time of the MRI study (►Fig. 6D–F).
Cerebellar Atrophy versus Cerebellar
Hypoplasia
CH refers to a cerebellum with a reduced volume, but a
normal shape resulting in cerebellar structures that are not
filling a normal or small posterior fossa (►Fig. 6, Supple-
mentary Material available in the online version only).48
CH is stable over time and is a common, nonspecific
neuroimaging finding that has been associated with highly
heterogeneous etiologies including both primary (malfor-
mative, genetic) and secondary (disruptive, acquired) le-
sions. Distinction between CA and CH seems not difficult in
theory, but can be problematic or impossible in practice
based on a single examination. In children with nonpro-
gressive cerebellar ataxia (i.e., with an obviously longstand-
ing static situation), enlarged cerebellar sulci mimicking CA
are often seen ( ►Fig. 7).49,50 It is questionable whether CA
or CH is the best term to refer to this neuroimaging pattern.
We prefer CH because of the nonprogressive course of
clinical and neuroimaging findings and favor a malforma-
tive instead of a degenerative pathomechanism. Otero et al
showed in a mouse model that compound conditional loss
Fig. 6 Discrepancy between clinical and neuroimaging course. (A) Sagittal, (B) axial, and (C) coronal T1-weighted images of a 14-year-old boy with
progressive cerebellar ataxia show marked enlargement of the cerebellar interfolial spaces compatible with cerebellar atrophy (CA). (D) Sagittal
T1-, (E) axial T1-, and (F) coronal T2-weighted images of the almost asymptomatic 11-year-old younger brother reveals an almost similar degree of
CA.
Cerebellar Atrophy in Children: An Update Poretti et al.
of cyclin A1/A2 results in increased apoptosis of neural
progenitors at early embryonic time. 51 This results in
decreased proliferation of cerebellar granule neuron pro-
genitors, Purkinje neuron dyslamination, and severe CH
and is similar to the nonprogressive enlargement of cere-
bellar interfolial spaces that we may see in children with
nonprogressive cerebellar ataxia.
In addition, CA may be superimposed to CH as shown in
some forms of PCH and some children with congenital
disorder of glycosylation type 1a.10,24
Finally, CA and CH are not always correctly used in the
medical literature and this adds to the confusion in terminology,
for example, PCH type 1 and 2 show a progressive atrophy of
cerebellum and brainstem, not a static hypoplasia.11
Conclusion
CA is a common, nonspecific finding in pediatric neurology and
neuroradiology. A neuroimaging based pattern-recognition ap-
proach in addition to patient and family history, clinical findings,
and results of additional investigations may (1) allow to make
the correct diagnosis, (2) narrow the list of differential diagnoses
and plan additional targeted investigations, (3) help the inter-
pretation of the results of laboratory investigations, and (4) in
the era of new generation sequencing allow the reevaluation of
the phenotype after the results of genetic tests (reverse pheno-
typing). Although the interpretation of CA and the differentiation
between CA and CH seem to be straightforward, discrepancies
between clinical and neuroimaging courses and potential
overlap between neuroimaging findings may make them very
challenging in the daily clinical work.
Neuropediatrics
Cerebellar Atrophy in Children: An Update Poretti et al.

Fig. 7 Cerebellar hypoplasia with enlarged interfolial spaces. (A) Sagittal and (B) coronal T2-weighted images of a 6-year-old girl with
nonprogressive cerebellar ataxia and developmental delay show a normal size of the cerebellum, but enlarged interfolial spaces mimicking
cerebellar atrophy. (C) Coronal T2-weighted image of a 4-year-old boy with nonprogressive cerebellar ataxia shows mild enlargement of the
cerebellar interfolial spaces. (D) Coronal T1-weighted image of the same child at the age of 16 years reveals unchanged mild enlargement of the
cerebellar interfolial spaces.

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Neurology, and Ianina Scheer, MD, Department of Diag-
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Switzerland, Thomas Schmitt-Mechelke, MD, Depart-
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