Differential diagnosis of cerebellar atrophy in childhood by juanrx

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Official Journal of the European Paediatric Neurology Society

Review article

Differential diagnosis of cerebellar atrophy in childhood Andrea Porettia, Nicole I. Wolfa,b, Eugen Boltshausera, a

Department of Paediatric Neurology, University Children’s Hospital of Zurich, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland Department of Paediatric Neurology, University Children’s Hospital of Heidelberg, Germany

art i cle info

ab st rac t

Article history:

Starting from the imaging appearance of cerebellar atrophy (CA) we provide checklists for

Received 31 May 2007

various groups of CA: hereditary CA, postnatally acquired CA, and unilateral CA. We also

Received in revised form

include a list of disorders with ataxia as symptom, but no evidence of CA on imaging. These

20 July 2007

checklists may be helpful in the evaluation of differential diagnosis and planning of

Accepted 26 July 2007

additional investigations. However, the complete constellation of clinical (including history and neurological examination), imaging, and other information have to be considered. On

Keywords: Cerebellar atrophy Cerebellar hypoplasia Children Neuroimaging Pattern-recognition

the basis of a single study distinction between prenatal onset atrophy, postnatal onset atrophy, and cerebellar hypoplasia is not always possible. Apart from rare exceptions, neuroimaging findings of CA are nonspecific. A pattern-recognition approach is suggested, considering isolated (pure) CA, CA and hypomyelination, CA and progressive white matter abnormalities, CA and basal ganglia involvement, and cerebellar cortex hyperintensity. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3.1. Diseases selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3.2. Personal experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Cerebellar atrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 4.1. Hereditary cerebellar atrophies (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 4.2. Acquired cerebellar atrophies (Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 4.3. Unilateral Cerebellar Atrophy (Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Ataxia without Cerebellar Atrophy (Table 5). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Note added in proof. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Corresponding author. Tel.: +41 44 266 73 30; fax: +41 44 266 71 63.

E-mail address: Eugen.Boltshauser@kispi.uzh.ch (E. Boltshauser). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.07.010

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Introduction

Neuroimaging plays a key role in diagnostic investigations in paediatric neurology, both in acute and chronic situations. A pattern-recognition approach has proven to be very helpful, e.g. in assessing white matter disorders. Here we focus on cerebellar atrophy (CA), and we provide checklists, which can serve as springboards in differential diagnosis. CA is a nonspecific finding in neuroimaging studies of children with a multitude of different conditions. Differential diagnosis comprises genetic and acquired causes. We have made an arbitrary grouping into diseases with hereditary CA due to metabolic and other genetic causes, disorders with postnatally acquired CA, and the rare conditions with unilateral CA. It is beyond the scope of this paper to review these disorders with respect to their clinical course, diagnostic criteria, and neuroimaging spectrum. Furthermore we included diseases with ataxia, but normal imaging. However, for other cerebellar alterations (e.g. cerebellar white matter involvement, white matter swelling, calcification, dentate nucleus changes, etc.) we refer to Steinlin et al.1 and standard neuroimaging textbooks.2,3

Neuroimaging

Atrophy, in general terms, implies (irreversible) loss of tissue. This may be reflected in an ongoing progressive course, until a final stage is reached, or it may result from a single event, e.g. an intoxication. 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 loss of tissue (Fig. 1). However, the term cerebellar hypoplasia (CH) describes a compact cerebellum with reduced volume, while cerebellar shape is (near) normal, the cerebellar structures are not filling a normally configurated posterior fossa, or a small cerebellum is found within a small posterior fossa (Fig. 2).4 Distinction of CA from CH does not seem difficult in theory, but can be problematic or impossible in practice based on a

12 (2008) 155 – 167

single examination. Effectively, in patients with non progressive congenital ataxia (i.e. with an obviously longstanding static situation) enlarged cerebellar sulci are often seen (Fig. 3).5–7 Separation of CA from CH is thus not always possible. In addition atrophy can be superimposed on hypoplasia, as documented in some patients with congenital disorder of glycosylation (CDG 1a).8 On the other hand, we do not always see progressive CA on imaging studies, even if there is a clearly progressive clinical course. There are several reasons for this finding: the atrophy might be very slowly progressive, e.g. over decades, and our imaging controls, especially in children, are performed in closer intervals. Or the atrophy might have taken place already in utero or before the first imaging study was performed, as in CA due to external causes as intoxication or irradiation, so that we can only see the final plateau. In nongenetic conditions as CA after cranial irradiation or viral infection we see the equivalent of this phenomenon: a rapid atrophy (sometimes reflected in the sudden onset of symptoms) is followed by a static phase. In medical literature, these two terms, CA and CH, are not always correctly applied, and this adds to the confusion in terminology, e.g. pontocerebellar hypoplasias 1 and 2 clearly show a progressive atrophy of cerebellum and brainstem, not a static hypoplasia.9 CA can be global or only involving either cerebellar vermis or hemispheres. Typically, CA is more pronounced in the vermis. Only in Unverricht–Lundborg disease, a form of progressive myoclonus epilepsy, the vermis is not significantly atrophic, whereas both cerebellar hemispheres show loss of bulk.10 The various imaging planes contribute to the evaluation of CA. The coronal sections are particularly informative: they provide an excellent overview of both vermis and hemispheres (predilection of involvement?, interfolial spaces?, signal changes of cerebellar white matter and cortex?). The sagittal sections are suitable to assess vermis atrophy, brainstem morphology, the size of the fourth ventricle, and the supravermian cistern, both being often dilated as a result of tissue loss due to CA. The axial sections are able to show enlarged interfolial spaces of both vermis and hemispheres (depending on level of section) and allow to judge for

Fig. 1 – Severe cerebellar atrophy in an 8-years-old child with ataxia teleangiectasia: (A) axial T2-weighted image shows symmetric atrophy of the cerebellar hemispheres and (B) midsagittal T1-weighted image shows atrophy of vermis (superior vermis more affected than the inferior).

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Fig. 2 – Five-year-old child with cerebellar hypoplasia: (A) coronal T1-weighted and (B) midsagittal T2-weighted images show reduced cerebellar volume but near normal structure.

Fig. 3 – Five-year-old child with nonprogressive cerebellar ataxia: (A) axial and (B) midsagittal images show a normal size of the cerebellum, but enlarged interfolial spaces mimicking cerebellar atrophy. MRI at 3 years was identical.

Fig. 4 – Six-year-old child with infantile neuroaxonal dystrophy: (A) midsagittal T1-weighted image shows severe vermis atrophy and enlargement of the fourth ventricle; (B) coronal FLAIR image shows symmetrical atrophy of the cerebellar hemispheres with hyperintensity of the cerebellar cortex; and (C) axial T2-weighted image shows hypointensity in both globi pallidi. compensatory enlargement of the fourth ventricle and the supravermian cistern, respectively. They are essential for the assessment of the supratentorial structures of interest, especially white matter (hypomyelination?, progressive white matter abnormalities?), cortex (atrophy?) and basal ganglia (atrophy?, signal changes?, calcification?). FLAIR images can falsely minimize the degree of CA, albeit they

are important in demonstrating signal changes of the cerebellar cortex, e.g. in infantile neuroaxonal dystrophy (INAD) (Fig. 4), which can be misinterpreted on T2-weighted images due to the hyperintense CSF surrounding the atrophic cortex.11 Data on 1H-MR spectroscopy in cerebellum are scarce, and in CA, voxel placing is difficult as they include CSF.

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3-Methylglutaconic aciduria

Wilson disease

Cockayne syndrome

Wilson disease (late)

hypomyelination (e.g. in Pelizaeus–Merzbacher disease, Mitochondrial disorders

Marinesco–Sjo¨gren syndrome

dystrophy

Mitochondrial disorders, other

ganglia and cerebellum

Mitochondrial disorders Hypomyelination with atrophy of the basal Kearns Sayre syndrome Infantile neuroaxonal

12 (2008) 155 – 167

It is remarkable that the vast majority of hereditary CA does not lead to significant brainstem atrophy, even in an advanced stage (Fig. 1). Some pontine atrophy may be seen in later stages of spinocerebellar ataxias. (SCA)12,13 Other exceptions to this ‘‘rule’’ are CDG1a8 and the group of pontocerebellar hypoplasias,9,14 which are in fact not hypoplasias in the strict sense, but prenatal onset degenerative disorders. This conservation of brainstem morphology in CA is in gross contrast to the neuroimaging findings in cerebellar disruptive processes including cerebellar agenesis. A pattern recognition approach will be helpful in the differential diagnostic evaluation (Table 1): an isolated CA (‘‘pure CA’’) is consistently found in a large proportion of hereditary CA (e.g. ataxia, teleangiectasia, ataxia-oculomotorapraxias, late onset GM2) (Fig. 1). Additional supratentorial findings (‘‘CA plus’’) should be systematically looked for, particularly:

Niemann–Pick disease type C Pelizaeus–Merzbacher like disease

Salla disease

Ataxia teleangiectasia like disorders

Late onset GM2

CA, cerebellar atrophy.

basal ganglia and cerebellum

Hypomyelination and atrophy of

Leukoencephalopathy with ataxia, hypodontia, and hypomyelination Ataxiaoculomotorapraxias

Salla disease, leukoencephalopathy with ataxia, hypodontia and hypomyelination, and syndrome with hypomyelination, atrophy of basal ganglia and cerebellum) (Fig. 5), periventricular progressive white matter abnormalities (a characteristic constellation in neuronal ceroid lipofuscinoses (NCL), Niemann–Pick disease type C) (Fig. 6), basal ganglia involvement, as atrophy, signal changes, and calcification (e.g. Cockayne syndrome, some mitochondrial disorders).

Methods

3.1.

Diseases selection

The conditions listed in Tables 2–5 have been compiled 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 have consulted textbooks on cerebellar disorders, ataxia disorders as well as on neuroimaging. We have collected literature reports with regard to cerebellar involvement. Pubmed was searched with appropriate key words. However, there are several potential problems and limitations in this way of compilation:

Dentatorubralpallidoluysian atrophy

Neuronal ceroid lipofuscinoses Pelizaeus–Merzbacher disease Ataxia teleangiectasia

Vanishing white matter disease

L-2-Hydroxyglutaric aciduria

Atrophy Calcifications Subcortical Periventricular

Diffuse

cortex T2hyperintensity

CA and cerebellar CA and progressive white matter abnormalities CA and hypomyelination Pure CA

Table 1 – Pattern-recognition approach: cerebellar atrophy ‘‘pure’’ and cerebellar atrophy ‘‘plus’’ (most prevalent diseases)

CA and basal ganglia involvement

Signal changes

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(a) CA may be only a feature at a very late stage of some diseases, (b) CA may be mentioned in single cases, not necessarily being representative of a particular condition, (c) CA is reported in texts but description of neuroimaging is poor and illustrations are lacking, (d) for particular disorders some references refer to ‘‘atrophy’’, while others quote ‘‘hypoplasia’’ (e.g. Cayman island ataxia, Marinesco–Sjo¨gren syndrome). Therefore the compiled lists are not meant to be lexical and complete, they rather represent ‘‘work in progress’’ and require future amendments and additions.

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Fig. 5 – Three-year-old child with Salla disease: (A) midsagittal T1-weighted image shows severe vermis atrophy, a thin corpus callosum, and a normal size of the brainstem and (B) axial T2-weighted image shows diffuse hyperintensity of the white matter as a sign of hypomyelination.

Fig. 6 – Three-year- and 6-month-old child with late-infantile neuronal ceroid lipofuscinoses: (A) axial and (B) coronal T2weighted images show symmetrical severe atrophy of the cerebellar hemispheres and slight atrophy of the cerebral cortex; and (C) axial T2-weighted image shows symmetrical hyperintensity of the periventricular white matter. Furthermore slight atrophy of the cerebral cortex.

3.2.

Personal experience

The absolute prevalence of most disorders with CA is not known. The relative prevalence may well be quite variable between different institutions, influenced by ethnicity, potential service to inbred populations, referral bias, and other factors. It may be of interest to include the author’s personal experience. We cared for patients with MRI documented CA and these diagnoses: Ataxia teleangiectasia (Fig. 1), ataxia with oculomotor apraxia type 1, CDG1a, Cockayne syndrome, GM2 gangliosidosis (late onset), INAD (Fig. 4), leukoencephalopathy with ataxia, delayed dentition and hypomyelination, NCL (late-infantile and juvenile)(Fig. 6), Niemann–Pick disease type C, mitochondrial disorders (various, incl. MELAS, Kearns–Sayre), metachromatic leukodystrophy, Pelizaeus– Merzbacher disease and Pelizaeus–Merzbacher-like disease, PEHO syndrome (Fig. 7), pontocerebellar hypoplasia type 2, and vanishing white matter disease. In addition we have seen numerous mainly sporadic, but also some familial cases of unexplained CA. The acquired conditions with CA in our patients include: prematurity, post cerebellitis, paraneoplastic (Langerhans cell

histiocytosis, opsoclonus–myoclonus syndrome), posterior fossa surgery, radiation therapy, vitamin B12 deficiency, phenytoin medication, and accidental intoxication (Fig. 8).

Cerebellar atrophy

4.1.

Hereditary cerebellar atrophies (Table 2)

This table gives an overview of genetic disorders with CA. We included OMIM numbers, time of clinical onset, onset of CA compared to clinical onset, the degree of CA, and in short, additional neuroradiological findings. The most important clinical findings are also integrated in order to facilitate differential diagnosis. Cerebellar signal changes are overall rare and usually involve the white matter. Additional to CA, T2-hyperintense cerebellar cortex is typical but not consistent for INAD (Fig. 4).11,15 However, this finding is not pathognomonic for INAD as assumed earlier, but can also be a characteristic sign of mitochondrial disorders, as complex I deficiency 16 and of Marinesco–Sjo¨gren syndrome.17 Other cerebellar abnormalities in addition to CA include hyperintensity of the dentate

160

Table 2 – Hereditary cerebellar atrophy in childhood listed according to disease onset (mitochondrial diseases are listed at the end) Disease

Onset of disease

Onset of CA

Frequency of CA

Degree of CA

Additional findings

Selected Reference

Neuroimaging

Clinical Extra, respiratory insufficiency, joint contractures, SMA Progressive micro, hyper, extra

607596

Neonatal

Early

Typical

Severe

Pontocerebellar hypoplasia

277470

Neonatal

Early

Typical

Severe

215100

Neonatal

Early

Occasional

Severe

Congenital cataract, MR, rhizomelia, epi, growth retardation, hyper

230400 312080

Late Late

Occasional Unknown

Mild Moderate

Liver failure, MR, epi, extra Nys, hypo, stridor, LATER hyper and extra

610377

Neonatal Birth–12 months 1–2 months

Pontocerebellar hypoplasia, mild CEA, delayed myelination T2Wm of the WM, delayed myelination, subependymal heterotopias Delayed myelination, CEA WM hypomyelination, CEA

Early

Typical

Severe

None

Hypo, MR, AT, febrile crises, retinal dystrophy

312170

1–2 months

Early

Typical

Severe

AT, weakness, failure to thrive, hypo, MR, micro

309400

1–6 months

Early

Occasional

Mild–severe

260565 212065

1–6 months 2–6 months

Late Early

Typical Typical

Severe Severe

604369

3–6 months

Late

Typical

Severe

Hypo, MR, sparse hair, elastic skin, hypopigmentation, hypothermia Epileptic EP, OA, oedema, hypo, micro Hypo, MR, AT, vm, inverted nipples, ascites, pericardial effusion AT, hypo, nys, RE

PEHO Congenital disorder of glycosylation type 1a Salla disease Cockayne syndrome

216400

6–12 months

Early

Typical

Severe

250950

6–12 months

Early

Typical

Severe

OA, AT, cutaneous photosensitivity, OA, cataracts, RE Epi, coma, vm, extra, MR, vomiting, hyper

3-Methylglutaconic aciduria Progressive cerebellocerebral atrophy Ataxia teleangiectasia

Dysgenesis of corpus callosum, CEA, T2Wm of striatum and thalami, delayed myelination Early CEA, tortuosity cerebral vessels, subdural hygromas None BS hypoplasia, WM atrophy or hypoplasia WM hypomyelination, BS atrophy, corpus callosum hypoplasia Calcification in BG and dentate nuclei, CEA T2Wm of BG, later global atrophy

6–12 months

Early

Typical

Severe

CEA

RE, epi, progressive spastic quadriplegia, micro

208900

6–12 months

Late

Typical

Severe

None

Marinesco-Sjo¨gren syndrome Neuronal ceroid lipofuscinoses, infantile Infantile-onset spinocerebellar ataxia (IOSCA) Hypomyelination with atrophy of the basal ganglia and cerebellum Infantile neuroaxonal dystrophy

248800

Before 12 months Before 12 months

Early

Typical

Severe

Early

Typical

Moderate

Cerebellar cortex T2Wm (inconsistent) CEA (more), T2Wm of WM, T2Wk of thalamus

AT, OMA, RE, nys, teleangiectasias, progeria, ovarian dysfunctions AT, MR, hypo, bilat. congenital cataract, hypogonadism Myo, micro, AT, extra, RE, visual failure (RP)

12 months

Late

Typical

Mild-severe

atrophy of BS and upper spinal cord, T2Wm of cerebellar WM

AT, epi, NP, extra, ophthalmoplegia, OA, female: primary hypogonadism

1–2 years

Early

Typical

Severe

Hypomyelination, atrophy of BG

MR, pale optic discs, hyper, extra, epi

1–2 years

Early

Typical

Severe

Cerebellar cortex T2Wm, pallidum T2 hypointensity

AT, RE, hyper, OA, nys

256600

52 8

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271245

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256730

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Pontocerebellar hypoplasia type 1 Pontocerebellar hypoplasia type 2 Rhizomelic chondrodysplasia punctata Galactosemia Pelizaeus–Merzbacher disease Mevalonate kinase deficiency Pyruvate dehydrogenase deficiency Menkes disease

OMIM

Mild

WM demyelination, corticosubcortical atrophy

AT, strabismus, hyper, neuropathy, RE

252650

1–5 years

Early

Typical

Mild–moderate

AT, hypo, MR, corneal clouding

2 years

Early

Typical

Moderate–severe

Hypoplasia of the corpus callosum, WM abnormalities Hypomyelination

AT, MR, hypodontia

270550

2–3 years

Early

Typical

Severe

Spinal cord atrophy

AT, neuropathy, hyper, retinal myelinated nerve fibers

607426

2–3 years

Early

Occasional

Severe

None

Heterogeneous

204500

2–4 years

Early

Typical

Severe

CEA (later), T2Wm of WM, T2 hypointensity of thalamus

Epi, myo, AT, extra, visual failure (RP), RE, micro

236792

2–4years

Late

Occasional

Moderate

AT, dementia, macro, pyramidal signs, epi

603896

2–6 years

Late

Typical

Moderate

2–10 years

Early

Typical

Severe

AT, hyper, RE, OA, epi, ovarian failure, cataracts, sudden deteriorations AT, OMA, extra, NP

208920

T2Wm of subcortical cerebral WM, nuclei dentate, putamen and globus pallidus T2 hypointensity and cystic degeneration of WM, BS atrophy None

604391

3–6 years

Late

Typical

Severe

None

AT, OMA

272800

3-7 years

Early

Typical

Moderate –severe

Mild CEA

AT, RE, hyper, extra, proximal weakness, behavioural symptoms

3–20 years 4–10 years

Late Late

Typical Typical

Moderate–severe Moderate

CEA, T2Wm of periventricular WM CEA (early, less), T2W hypointensity thalamus

AT, hyper, MR, dystonia, nys RP, RE, epi, myo, AT, extra

204200

222300

First decade

Late

Occasional

Moderate

183086

first-second decade

Early

Typical

Moderate–severe

Diabetes mellitus and insipidus, nys, OA, AT, epi, deafness, myo, hyporeflexia, retarded growth Episodic ataxia, hemiplegic migraine

CACNA1A-Mutation (including SCA6, Episodic ataxia type 2, Familial hemiplegic migraine 1) Juvenile DRPLA

Atrophy of hypothalamus and cerebral cortex, hyperintensity of neurohypophysis None

125370

First–second decade

Early

Typical

Severe

Progressive myoclonic epilepsy, RE, AT

Myoclonic epilepsy of Unvvericht and Lundborg Wilson disease

254800

First–second decade

Late

Typical

Moderate

T2Wm of globi pallidi and periventricular WM, atrophy of tegmentum, especially midbrain and superior pons CEA, atrophy of pons and medulla

AT, mild MR, progressive myoclonic epilepsy

277900

After 10 years

Late

Occasional

Mild

Kayser-Fleischer ring, dystonia, liver failure,

604360

Second decade

Late

Typical

Moderate

Progressive weakness and hyper of lower extremities, AT, extra, MR, NP

Leukoencephalopathy with ataxia, hypodontia, and hypomyelination Autosomal recessive spastic ataxia of Charlevoix-Saguenay Coenzyme Q10 deficiency Neuronal ceroid lipofuscinoses, late infantile L-2-Hydroxyglutaric aciduria Vanishing white matter disease Ataxia-oculomotor apraxia type 1 Ataxia teleangiectasia like disorder (ATLD) Late-onset GM2 gangliosidosis

268800 Portneuf spastic ataxia Neuronal ceroid lipofuscinoses, juvenile Wolfram syndrome (DIDMOAD)

Hereditary spastic paraplegia and thin corpus callosum

108500 141500

T2Wmof the putamen, and cortical WM, Panda’s sign, CEA Thin corpus callosum (corpus and genu), CEA

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Occasional

161

Late

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1–2 years

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250100

Infantile metachromatic leukodystrophy Mucolipidosis type IV

162

Table 2 (continued ) Disease

Onset of CA

Frequency of CA

Degree of CA

Additional findings

Selected Reference

Neuroimaging

Clinical

Early

Typical

Severe

None

AT, nys, NP, extra, OMA

Early

Typical

Severe

None

Dystonia, AT, nys

Late

Typical

Moderate–severe

None

Epi, myo, pyramidal signs, AT, MR

variable

Variable

Early

Typical

Severe

Atrophy of BS and spinal cord

AT, hyper, nys, ev. myopathy, ev. RP

12,13

300100

Variable

Late

Occasional

Moderate–severe

Variable

Early

Typical

Moderate

AT, hyper, RE, personality changes, visual deficits, adrenal insufficiency AT, epi, vm, vertical gaze paralysis, extra, dementia

257220

T2Wm of cerebellar hemispheres, WM, and BS, CEA, BS atrophy CEA, T2Wm of the periventricular WM

All age groups

Variable, usually late

Unknown

Involvement of BG and WM or T2Wm cerebellar cortex possible

20,21

Depending on mutant load; usually 5–15 years First–third decade, usually 5–15 years 5–15 years

Unknown

Moderate

Symmetric T2Wm of BS and BG

All systems may be involved: epi, muscle weakness, RE, hearing loss, ophthalmoplegia, short stature, AT, OA, hyper, stroke like episodes NP, AT, RP, epi, RE

Late

Occasional

Mild

Severe cortical atrophy, stroke-like lesions (mostly occipital)

Stroke-like episode, partial epi, dementia, short stature, diabetes mellitus

Late

Typical

Moderate

Unknown

Myopathy, external ophthalmoplegia, AT, RP, heart block, MR, diabetes mellitus AT, nys, epi, extra, ophthalmoplegia, NP, liver involvement in Alpers disease

Variable, depending on mutation

CEA, T2Wm of WM, thalami and BG, calcification of BG T2Wm of the posterior thalami, nuclei dentate, inferior olives and occipital cortex

Mitochondrial disorders (in general)

Neuropathy, ataxia, and retinitis pigmentosa (NARP)

551500

MELAS

540000

Kearns–Sayre syndrome (KSS) Polymerase g mutations

530000 174763

AT, ataxia; BG, basal ganglia; BS, brain stem; CEA, cerebral atrophy; CSF, cerebrospinal fluid; EP, encephalopathy; epi, seizures; extra, extrapyramidal signs; hyper, muscular hypertonia; hypo, muscular hypotonia; macro, macrocephaly; micro, microcephaly; MR, mental retardation; myo, myoclonias; NP, neuropathy; nys, nystagmus; OA, optic atrophy; OMA, oculomotor apraxia; RE, regression; RP, retinitis pigmentosa; SMA, spinal muscular atrophy; T2Wm, hyperintensity in T2 weighted images; T2Wk hypointensity in T2 weighted images; vm, visceromegaly; WM, white matter.

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Second–third decade Second–third decade Second–third decade

606002

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Niemann-Pick disease type C

Onset of disease

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Ataxia-oculomotor apraxia type 2 Predominant dystonia with CA Familial adult myoclonic epilepsy type 3 Spinocerebellar ataxias (SCA), more than 25 types Adrenoleukodystrophy

OMIM

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163

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Table 3 – Acquired cerebellar atrophy in childhood Condition

Extreme prematurity Neonatal hypoxic-ischaemic encephalopathy Post ‘‘inflammatory’’ ( ¼ post ‘‘cerebellitis’’) Multiple sclerosis Post-traumatic brain injury Paraneoplastic

Paediatric Hodgkin disease Langerhans cell histiocytosis Opsoclonus–myoclonus syndrome

Chronic epilepsy Radiation therapy

Comments

Selected References

Risk factors: GAo30 weeks, IVH Full term, superior vermis atrophy

Exceptional observations, often clinically ‘‘silent’’

Brainstem also affected, possible in adolescents Moderate–severe trauma, global atrophy Rare, diffuse cerebellar dysfunction Global atrophy CA as late sequelae

Not due to AED intoxication

90 91 92 93

Personal experience Personal experience

Posterior fossa surgery Malnutrition

Vitamin B12 deficiency

Mostly related to breastfeeding in vegan mothers, cerebral 4 CA

Phenytoin and other AED Tacrolimus Accidental intoxication

Children, adolescents Children, adolescents Children, adolescents

Alcohol, solvents, heavy metals, drugs

Adolescents

Toxic 95

Personal experience 96,97

AED, antiepileptic drugs; CA, cerebellar atrophy; GA, gestational age; IVH, intraventricular haemorrhage.

Table 4 – Unilateral cerebellar atrophy in childhood Condition

Comments

Selected References

Unilateral cerebellitis

Cerebellitis has usually bilateral involvement, rare unilateral Rare isolated, different aetiologies: embolic, traumatic, toxic

Unilateral ischaemic infarction Unilateral traumatic brain injury/concussion Following posterior fossa surgery Crossed cerebrocerebellar diaschisis Unexplained origin

Personal experience Personal experience Unilateral CA contralateral to a supratentorial lesion of different aetiology Child with epilepsy

CA, cerebellar atrophy.

nucleus as in L-2-hydroxyglutaric aciduria 18 or white matter abnormalities in patients with cerebrotendinous xanthomatosis.19 Mitochondrial disorders are often present with ataxia, and usually additional neurological signs are present. Sometimes

it is straightforward to make a clinical and subsequent molecular diagnosis as in Kearns–Sayre syndrome or NARP syndrome, but in the majority of affected children, there is a nonspecific encephalomyopathy. MRI features can also vary and include CA, involvement of basal ganglia and brainstem, supra- and infratentorial white matter signal changes, and signal changes of the cerebellar cortex alone or in combination as well as normal imaging.16,20 Coenzyme Q10 (CoQ10) deficiency is a heterogeneous group of different clinical variants encompassing both primary and secondary forms.21 Three genes (PDSS1, PDSS2, and COQ2) have been found to be involved in CoQ10 biosynthesis and cause primary CoQ10 deficiency. Mutations in these genes have been associated with the earliest and most severe variant of CoQ10 deficiency, infantile mitochondrial encephalomyopathy of which ataxia is not a feature. However, there is a wide clinical heterogeneity within this group of disorders. Twenty-eight dominantly inherited SCAs12,13 have now been described, and present mainly in adults. Early onset of paediatric phenotypes recognized include SCA-2 22 and SCA-7.23,24 Childhood and adolescent onset presentations of ataxia with faster progression occur in SCA-1 25 and SCA-3. Severe childhood phenotypes are rarely described also for SCA-4, SCA-6, and SCA-11. The main distinguishing features are retinitis pigmentosa in SCA-7 and very slow saccades in SCA-2 and SCA-3. SCA-6 also differs from the other dominant ataxias, with the gene (CACNA1A) being a membrane-bound voltage-dependent calcium channel subunit, and it has a

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Table 5 – Diseases with ataxia without cerebellar atrophy in childhood Disease

OMIM

Non-progressive congenital ataxias Friedreich ataxia Vitamin E deficiency Refsum disease Abetalipoproteinaemia Glucose transporter 1 deficiency

229300 277460 266500 200100 606777

Angelman syndrome Rett syndrome

105830 312750

Comments

Selected References

AT, speech impairment, MR

Cervical cord atrophy, AT, sensory NP, hypertrophic cardiomyopathy Low serum vitamin E, AT, sensory NP Elevated phytanic acid, RP, AT, chronic NP, cataract Very low cholesterol, diarrhoea, acanthocytosis, AT, sensory NP Hypoglycorrhachia, acquired micro, infantile epi, delayed development MR, AT, abnormal behaviours, epi, micro, absent speech Dementia, autism, hand stereotypies, AT, acquired micro

40 40 40 40 41

42 43

AT, ataxia; CA, cerebellar atrophy; epi, epilepsy; micro, microcephaly; MR, mental retardation; NP, neuropathy; RP, retinitis pigmentosa.

Fig. 7 – Serial sagittal T2-weighted MR imaging of a child with PEHO syndrome: (A) at 5 months MRI shows a normal cerebellar structure; (B) at 4 years and 6 months MRI shows a severe cerebellar atrophy, enlarged fourth ventricle, and supravermian cistern. No pontine atrophy.

Fig. 8 – Serial coronal T2-weighted MR imaging of a child with accidental heroin intoxication: (A) at 3 years in the acute phase MRI shows hyperintensity of the cerebellar cortex as well as widespread signal changes in the cerebral white matter and (B) 3 months later MRI shows symmetrical atrophy of the cerebellar hemispheres and supratentorial leukoencephalopathy. smaller range of repeat expansion length in disease-associated patients. Mutations (nonsense mutations, missense mutations, deletions, and insertions) in the same gene lead to familial hemiplegic migraine type 1 and episodic ataxia type 2

with different clinical phenotypes, but CA is often seen in affected individuals.26 CA was also rarely reported in single cases of the following conditions, not included in Table 2: succinic semialdehyde

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dehydrogenase deficiency,27 cerebrotendinous xanthomatosis,19 nonketotic hyperglycinaemia,28 early-onset combined methylmalonic aciduria and homocystinuria,29 Pallister– Kilian syndrome,30 Galloway–Mowat syndrome,31 trichothiodystrophy,32 and as late observation in Canavan disease.33

4.2.

Acquired cerebellar atrophies (Table 3)

In this context ‘‘acquired CA’’ refers to postnatally acquired conditions, i.e. causes of prenatal cerebellar tissue loss (e.g. toxins, teratogens, prenatal viral infections) are deliberately not considered. We focus on observations in childhood (including adolescence), the prevalence and spectrum of CA due to toxic and paraneoplastic origin are obviously different in adulthood. An accidental intoxication in a toddler resulting in CA is shown in Fig. 8. CA resulting from antiepileptic drugs, particularly phenytoin, is well known.34 It is still debated whether (and how) CA can result from chronic, not treatment-refractory epilepsy.35

4.3.

Unilateral Cerebellar Atrophy (Table 4)

We refer to unilateral CA as postnatally acquired situations. This contrasts to unilateral CH as a result of a prenatal disruption (cerebellar haemorrhage, ischaemic lesion).4 Distinction should not be problematic within the clinical context. Unilateral CA is a very rare finding. It may be observed subsequent to an obvious preceding event (‘‘insult’’),36 e.g. following concussion or unilateral cerebellitis.37 A case of progressive unilateral CA in a child with epilepsy was presented by Strobl et al.38 While functional cerebro-cerebellar diaschisis is a well-known phenomenon, demonstrable with functional MRI and positron emission tomography (PET), crossed cerebro-CA is a rare finding.39

Ataxia without Cerebellar Atrophy (Table 5)

Ataxia, even if clinically progressive, is not synonymous with CA. Table 5 summarizes disorders with ataxia as an important sign, but without evidence of CA on neuroimaging. Remarkably the relevant treatable metabolic ataxias (Refsum, vitamin E deficiency, abetalipoproteinaemia) are among these diseases.40 However the diagnosis of these conditions is straightforward with established metabolic investigations (phytanic acid in serum, serum vitamin E, and hypocholesterinaemia as screening tests, respectively). Friedreich ataxia goes along with cervical cord atrophy.40 Glucose transporter deficiency has consistently normal imaging.41 Atypical Rett syndrome as well as Angelman syndrome may initially mimic congenital ataxia, MRI reveals normal neuroanatomy.42,43 Nonprogressive congenital (cerebellar) ataxias often have normal cerebellar structures on imaging (Fig. 3).44 The congenital ataxias are likely to be a heterogeneous condition. Although familiar occurrence is observed, the responsible genes are not yet known. Fragile X-associated tremor/ataxia syndrome (FXTAS) is not yet documented before adulthood. In affected individuals, neuroimaging features include cerebellar bilateral white matter lesions, but not striking CA.45

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165

Conclusion

CA is a nonspecific neuroimaging finding in children with diverse neurological disorders. MRI changes can show isolated CA or other features including brainstem atrophy or supratentorial white matter changes. Sometimes, these associated imaging changes allow one to make a diagnosis. More often, history and results of additional investigations are needed to reach a final conclusion. Approach should take into account the clinical course (progressive versus nonprogressive, additional signs) in addition to the imaging results in order to plan the appropriate investigations and interpret their results.

Note added in proof Since submission we have seen a fifteen-year-old teenager with Huntington disease and MRI evidence of cerebellar atrophy. This has been previously reported (Fennema-Notestine C, Archibald SL, Jacobson MW, et al. In vivo evidence of cerebellar atrophy and cerebral white matter loss in Huntington disease. Neurology 2004;63:989–95).

Acknowledgements We thank Prof. Dr. Thierry A. Huisman, Department of Diagnostic Imaging, University Children’s Hospital of Zurich, Switzerland, and Drs. Angelika Seitz and Inga Harting, Department of Neuroradiology, University Hospital of Heidelberg, Germany for allowing us to show the MR-images. 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. R E F E R E N C E S

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