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 8 ( 2 0 1 4 ) 2 4 9e2 5 6

Official Journal of the European Paediatric Neurology Society

Review article

Subthalamic nucleus involvement in children:A neuroimaging pattern-recognition approach

Thangamadhan Bosemani a, Cristina Anghelescu b, Eugen Boltshauser c,Alexander H. Hoon Jr.d,e, Phillip L. Pearl f, Dana Craiu b,g,Michael V. Johnston d,e,h, Thierry A.G.M. Huisman a, Andrea Poretti a,c,*a 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, MD, USAb Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, RomaniacDepartment of Pediatric Neurology, University Children’s Hospital, Zurich, SwitzerlanddKennedy Krieger Institute, Baltimore, MD, USAeDepartment of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USAfDivision of Neurology, Children’s National Medical Center, Washington, DC, USAgDepartment of Neurology, Pediatric Neurology, Neurosurgery, Psychiatry, “Carol Davila” University of Medicine,

Bucharest, RomaniahDepartment of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

a r t i c l e i n f o

Article history:

Received 16 April 2013

Received in revised form

17 September 2013

Accepted 30 September 2013

Keywords:

Magnetic resonance imaging

Pattern-recognition approach

Subthalamic nucleus

Children

* Corresponding author. Section of PediatricRadiology and Radiological Science, The JohnZayed Tower, Room 4174, 1800 Orleans Stre

E-mail address: aporett1@jhmi.edu (A. Po1090-3798/$ e see front matter ª 2013 Europhttp://dx.doi.org/10.1016/j.ejpn.2013.09.010

a b s t r a c t

A neuroimaging-based pattern-recognition approach has been shown to be very helpful in

the diagnosis of a wide range of pediatric central nervous system diseases. Few disorders

may selectively affect the subthalamic nucleus in children including Leigh syndrome,

succinic semialdehyde dehydrogenase deficiency, kernicterus, chronic end-stage liver

failure and near total hypoxic-ischemic injury in the full-term neonates. The consideration

of the constellation of clinical history and findings as well as additional neuroimaging

findings should allow planning the appropriate diagnostic tests to make the correct diag-

nosis in children with involvement of the subthalamic nucleus.

ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2502. The subthalamic nucleus (STN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2503. Leigh syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department ofs Hopkins University School of Medicine, Charlotte R. Bloomberg Children’s Center, Sheikhet, Baltimore, MD 21287-0842, USA. Tel.: þ1 4109556454; fax: þ1 4105023633.retti).ean Paediatric Neurology 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 8 ( 2 0 1 4 ) 2 4 9e2 5 6250

3.1. Leigh syndrome due to COX deficiency with SURF1 mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2513.2. Leigh syndrome due to complex I deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

4. Succinic semialdehyde dehydrogenase deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2535. Kernicterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2536. Hepatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2547. Hypoxic-ischemic injury in term neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2548. Other diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2559. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

1. Introduction 2. The subthalamic nucleus (STN)

Neuroimaging plays a key role in diagnostic investigations

and classification of diseases in pediatric neurology. The uti-

lization of a neuroimaging-based pattern-recognition

approach was first shown to be beneficial in the diagnosis of

white matter diseases by Marjo van der Knaap and Jaap Valk

in 1991.1 Subsequently, a neuroimaging-based pattern-recog-

nition approach was demonstrated to provide important in-

formation in assessing children with cerebellar atrophy,2

abnormalities of the dentate nucleus3 or intracranial calcifi-

cations.4 This approach enables us to create “neuroimaging

phenotypes”, which are helpful in identifying disease entities

or plan further targeted clinical, laboratory or genetic in-

vestigations to establish the correct diagnosis.

In this paper, we are focusing on the subthalamic nucleus

(STN). Involvement of the STN has been extensively described

in adults with movement disorders, particularly Parkinson

disease and neurosurgery using deep brain stimulation.5 The

role of the STN in children and its involvement in pediatric

neurological disorders, however, has been seldom reported.

After a short introduction about anatomy and function of the

STN in children, we will discuss the neuroimaging findings of

pediatric neurological disorders with involvement of the STN,

which have been selected on the basis of our experience and

with review of the literature using appropriate key words

(magnetic resonance imaging; pattern-recognition approach;

subthalamic nucleus; children).

Fig. 1 e Coronal T2-weighted images in a healthy (A) 9-month-o

located laterally to the hypointense red nucleus andmedially to

of the STN progressively decreases due to increasing iron depo

The STN is an almond shaped structure with a rostrocaudal

length of about 10 mm, situated in the most caudal part of the

diencephalon. The posterior limb of the internal capsule is on

its anterolateral border separating it from the globus pallidus

(GP) laterally; the fields of Forel (H1 andH2) and hypothalamus

(with which the borders are blurred) are on its medial border;

the substantia nigra (SN) is partially inferior andmedial to the

STN; the red nucleus posteromedially, and the zona incerta

and lenticular fasciculus are dorsally (superior and medial)

positioned.6,7

The STN is a key structure in the basal ganglia circuit and

serves as an important relay station within the cortico-

striothalamocortical circuit.7 It projects to both the external

and internal parts of the GP (tractus subthalamicus), to the

reticular part of the SN, striatum, cerebral cortex, substantia

innominata, pedunculopontine nucleus, and mesencephalic

and pontine reticular formation. Pallido-subthalamic con-

nections are well established. The STN receives its main

afferent inputs from the globus pallidus externus (GPe).

These afferents are GABAergic and have an inhibiting effect

on the STN. The efferent axons from the STN are gluta-

matergic and have an excitatory effect on the globus pallidus

internus (GPi).

On conventional MRI, the normal appearance of the STN

changes as myelination progresses in the first years of life. At

term, the normal STN on T1-weighted images is moderately

ld infant and (B) 12.5-year-old child show the STN (arrows)

the hypointense corticospinal tract. Over time, the T2 signal

sition.

Fig. 2 e 3-year-old child with Leigh disease due to COX I deficiency and SURF1 mutation: (A) axial, (B) coronal and (C)

parasagittal T2-weighted images shows T2-hyperintense signal abnormality in the STN (arrows), substantia nigra

(arrowhead in A), putamina (arrowhead in B), GP (asterisk in B) and periaqueductal gray matter (asterisk in A).

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 8 ( 2 0 1 4 ) 2 4 9e2 5 6 251

hyperintense to the adjacent unmyelinated white matter.8

Hyperintensity on T1-weighted imaging is caused by various

factors, primarily the paramagnetic effect and immobilization

of water molecules. The former includes metal ions, melanin,

or free radicals; the latter includes concentrated solutions of

proteins, calcified tissue, and lipids. Additionally, glia forma-

tion or glial reaction may play a role in neonatal STN

hyperintensity.8

The T1-hyperintensity diminishes and disappears over

time and the STN becomes difficult to distinguish from the

surrounding white matter on T1-weighted images. On T2-

weighted images, the normal STN becomes progressively

hypointense due to increasing iron deposition.6 Hypointensity

on T2-weighted images is more prominent at high field

strength because of the increased susceptibility effect of iron

(Fig. 1).

3. Leigh syndrome

Leigh syndrome (LS, OMIM 256000) or subacute necrotizing

encephalomyelopathy represents a heterogeneous group of

neurodegenerative disorders. It is defined by characteristic

symmetric involvement of basal ganglia, midbrain, dentate

nuclei and, occasionally, cerebral white matter.9,10 The

affected infants and children typically present toward the end

of first year of life with muscular hypotonia, failure to thrive,

motor and cognitive regression, ataxia, dystonia, and oph-

thalmoplegia.9 LS is heterogeneous from a clinical, neuro-

imaging and genetic standpoint including mutations in both

mitochondrial and nuclear encoded genes, which code for

proteins of the respiratory chain complexes I, II, III, IV and V,

mitochondrial tRNA, pyruvate dehydrogenase complex and

coenzyme Q10.9,11

The neuroimaging phenotype in LS varies with the un-

derlying genotype. The involvement of the STN has been re-

ported in LS patients with 1) cytochrome c oxidase (COX)

deficiency with SURF1 mutation12,13 and 2) complex I

deficiency.14

3.1. Leigh syndrome due to COX deficiency with SURF1mutation

COX deficiency is the most common cause of LS.15 COX or

complex IV of the respiratory chain is composed of 13 struc-

tural subunits, 3 of which are encoded by mitochondrial DNA

(mtDNA) and the remainder by nuclear DNA (nDNA). Loss-of-

function mutation in one of these nuclear genes, SURF1, is the

most common cause of COX-deficient LS.16

Bilateral STN involvement as T2- and FLAIR-hyperintense

signal abnormality is a very common neuroimaging finding

in COX-deficient LS with underlying SURF1 mutations

(Fig. 2).12,13,17 The common additional neuroimaging findings

in children with COX-deficient LS due to SURF1 mutation

include T1-hypointense and T2- and FLAIR-hyperintense

signal abnormalities in the inferior olivary nuclei and nuclei

of the solitary tracts in the lower brain stem, inferior cere-

bellar peduncles, central tegmental tracts and reticular for-

mation in the dorsal pons and periaqueductal gray matter in

themidbrain.12,13,18,19 Involvement of the substantia nigra, red

nuclei, and dentate nuclei is less common, while the medial

thalami are uncommonly affected.12,13,18,19

3.2. Leigh syndrome due to complex I deficiency

Complex I (NADH: ubiquinone oxidoreductase) is the largest

component of the oxidative phosphorylation system and is

composed of at least 45 subunits, seven of which are encoded

by mtDNA.20 Isolated complex I deficiency is the most com-

mon etiology for respiratory chain defects in children and

accounts for various clinical phenotypes including not only

LS, but also Leber hereditary optic neuropathy (LHON), mito-

chondrial encephalomyopathy, lactic acidosis and stroke-like

episodes (MELAS), and numerous other clinical presentations

combining hypotonia, developmental delay, seizures, cardio-

myopathy, optic atrophy or retinopathy and other organ

involvement.21

Bilateral STN involvement as T2- and FLAIR-hyperintense

signal abnormality is a common finding in complex I

Fig. 3 e 23-month-old child with Leigh disease due to Complex I deficiency and MTND5 mutation: (A) coronal T2-weighted

image showsT2-hyperintense signal abnormality in the left STN (arrow), substantia nigra (arrowhead) and thalami; (B, C) axial

T2-weighted images show T2-hyperintensity of the dorsal midbrain (arrow in B) and bilateral, markedly swollen, inferior

olivary nuclei (arrows in C); (D) coronal T2-weighted image shows T2-hyperintense signal abnormality in the swollen, inferior

olivary nuclei (arrows) and central tegmental tracts (arrowheads) connecting the inferior olivary nuclei with the red nuclei.

Fig. 4 e 2.5-year-old child with Leigh disease due to Complex I deficiency: (A) axial and (B) coronal T2-weighted images

show T2-hyperintense signal abnormality in the swollen STN (arrows).

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Fig. 5 e 10 year-old child with SSADHD: (AeC) Coronal short tau inversion recovery images show bilateral symmetric

homogenous signal abnormalities in the lateral (white arrowheads in A, B) and medial (black arrowheads in A) parts of the

GP, STN (black arrows in B) and dentate nuclei (white arrows in C). (Reprinted with permission from Pearl et al., Neurology

2009; 73:423e9).

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deficient LS and is more frequently observed in children car-

rying mtDNA than in nuclear mutations (Figs. 3 and 4).12,13,17

In particular, STN involvement was reported in children

with complex I deficiency due to mutations in MTND1,22

MTND3,23 MTND524 and MTND6.25 Additional neuroimaging

findings in complex I deficiency include T1-hypointense and

T2- and FLAIR-hyperintense, symmetric signal abnormalities

in the brain stem affecting the substantia nigra, peri-

aqueductal gray matter, mamillothalamic and spinothalamic

tracts, medial lemniscus andmedial longitudinal fasciculus.14

Signal abnormalities of the putamen, caudate, pallidum, and

dentate nuclei are also frequent.14 A diffuse supratentorial

leukoencephalopathy involving the deep lobar white matter

has been observed only in patients with nDNA mutations,

while cerebellar atrophy and supratentorial stroke-like le-

sions were only observed in complex I deficient patients car-

rying mtDNA mutations.14

4. Succinic semialdehyde dehydrogenasedeficiency

Succinic semialdehyde dehydrogenase deficiency (SSADHD,

OMIM 271980) or 4-hydroxybutyric aciduria is a rare, auto-

somal recessive disease in the degradation pathway of

gamma-amino butyric acid (GABA) due to mutations in the

ALDH5A1 gene.26,27 Childrenwith SSADHD typically present in

the first years of life with mild-moderate intellectual

disability, disproportionate language impairment, hypotonia,

hyporeflexia, autistic behaviors, seizures, and

hallucinations.27

Bilateral, symmetric T2-hyperintense signal abnormality

of the STN is an occasional finding in SSADHD (Fig. 5).28

Neuroimaging findings in SSADHD typically include sym-

metric increased T2-signal in the globi pallidi and dentate

nuclei.27,29 Other occasional neuroimaging findings are T2-

hyperintense signal of the subcortical white matter and

diffuse cerebral and cerebellar atrophy.28

5. Kernicterus

Kernicterus is a pathological term that describes yellow

staining of the deep gray nuclei of the brain due to markedly

increased level and deposition of unconjugated bilirubin in

the neonatal period.30 Brain injury due to hyperbilirubinemia

selectively affects the STN, GP, substantia nigra, hippocam-

pus, and brain stem auditory, vestibular and oculomotor

nuclei.31 Red blood cell hemolysis is the most common etiol-

ogy of hyperbilirubinemia, but several other causes are also

well known.32 Additionally, in the presence of predisposing

factors (e.g. prematurity, sepsis, acidosis), kernicterus may

occur even at a lower level of bilirubin.32

Newborns with acute bilirubin encephalopathy typically

present with poor feeding, lethargy, high-pitched cry, irrita-

bility, seizures and abnormalities of muscular tone such as

hypotonia alternating with hypertonia and opisthotonus.

Clinical findings of chronic bilirubin encephalopathy consist

of dyskinetic movement disorders (athetosis and dystonia),

deafness or hearing loss due to auditory neuropathy, impair-

ments of upward gaze, and enamel hypoplasia of the decid-

uous teeth.30 Athetosis and dystonia most likely result from

disinhibition of the thalamus because destroying the output of

the GP reduces inhibitory input to the motor thalamus.33

In acute neonatal bilirubin encephalopathy, the STN ap-

pears symmetrically hyperintense on T1-weighted images.34

Another key neuroimaging finding is symmetric T1-

hyperintense signal abnormality in the GP.33,34 This may

reflect astroglial cell germinocystic reaction of the acute

event; additionally, edema and bilirubin itself may contribute

in the hyperacute stage.34 The signal intensity of the GP on T2-

weighted images is commonly normal, but may also be

hyperintense in rare cases.33e35 Additionally, T2-hyperintense

and T1-hypointense signal of periventricular and subcortical

white matter has been described.36 Loss of the T1-

hyperintense signal in the GP and STN occurs between the

first and third week after the acute event.34 In the chronic

phase, T2- and FLAIR-hyperintense signal abnormality of the

Fig. 6 e 15-year-oldmale with CriglereNajjar disease and dyskinetic cerebral palsy secondary to kernicterus: (A, B) axial and

(C) coronal T2-weighted images show T2-hyperintense signal in both STN (arrows) and GP (arrowheads).

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 8 ( 2 0 1 4 ) 2 4 9e2 5 6254

GP is an almost universal finding and T2- and FLAIR-

hyperintense signal of the STN, hippocampi, and cerebral

white matter may be also seen (Fig. 6).37e39

6. Hepatic encephalopathy

Hepatic encephalopathy (HE) is a serious, but uncommon

complication of acute (e.g. fulminant viral hepatitis and

ingestion of drugs and toxins) or end-stage, chronic (e.g.

biliary atresia, Wilson’s disease, autoimmune chronic active

hepatitis and Reye’s syndrome) liver diseases in children. HE

is characterized by an altered mental state, pyramidal tract

dysfunction and extrapyramidal movement disorders.40 The

pathogenesis of HE is not completely understood. Ammonia,

glutamine and manganese as neurotoxins have been impli-

cated in HE. In the acute setting of HE, neuroimaging has only

a limited value in excluding an underlying intracranial pa-

thology, such as intracranial hemorrhage which may account

for the patient’s symptoms.41

In pediatric, non-Wilsonian, chronic hepatic failure, con-

ventional MRI may reveal symmetric, hyperintense signal on

T1-weighted images in the STN, GP and substantia nigra with

no corresponding signal abnormalities on T2-weighted im-

ages (Fig. 7).42 Themost likely explanation for the increased T1

signal intensity is a rise in manganese concentration (a

paramagnetic substance) in the CNS, with selective deposition

in the GP, substantia nigra and STN.43 Diffuse cortical T2-

hyperintense signal with sparing of the perirolandic and oc-

cipital regions may be also seen.44

Fig. 7 e 18-year-old young man with short gut syndrome,

chronic liver failure and parenteral nutrition presents with

hepatic encephalopathy: coronal T1-weighted image

shows hyperintense signal in both STN (left more than

right, arrows) and GP (arrowheads).

7. Hypoxic-ischemic injury in term neonates

Hypoxic-ischemic injury (HII) occurs in 1e6 of every 1000 live

full-term neonates and carries a high-risk for subsequent

motor, intellectual and behavioral disabilities.45 The neuro-

imaging pattern of injury and outcome is related to the cause

and severity of the injury.46,47 In term neonates with mild to

moderate prolonged asphyxia, the vascular watershed zones

(anterior-middle and posterior-middle cerebral arteries) are

involved, affecting whitematter and inmore severely affected

newborns the overlying cortex presenting as multicystic

encephalomalacia.46

Bilateral T2- and FLAIR-hyperintense signal of the STN

have been occasionally reported in ex-full-termneonateswith

spastic or dyskinetic cerebral palsy after acute near total

asphyxia.48 In the acute phase, STN involvement is charac-

terized by T1-hyperintense, T2-hypointense and restricted

diffusion. In full-term neonates with an acute sentinel event

Table 1 e Pattern-recognition approach of STN involvement in children.

Disease STN GP Striatum SN Thalamus CTT ION DN

LS due to SURF1 mutation þ � þ � � þ þ �LS due to complex I deficiency þ þ þ þ � � � þSSADHD þ þ � � � � � þKernicterus þ þ � � � � � �HE þ þ � þ � � � �HII þ � þ � þ � � �

CTT, central tegmental tract; DN, dentate nucleus; GP, globus pallidum; HE, hepatic encephalopathy; HII, hypoxic -ischemic injury; ION, inferior

olivary nucleus; LS, Leigh syndrome; SN, substantia nigra; STN, subthalamic nucleus; SSADHD, succinic semialdehyde dehydrogenase

deficiency.

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 8 ( 2 0 1 4 ) 2 4 9e2 5 6 255

such as a ruptured uterus, placental abruption or a prolapsed

cord, however, the ventrolateral thalami, posterior putamina,

hippocampi and bilateral perirolandic cortex are predomi-

nantly affected.46

8. Other diseases

A small cavernous angioma in the left STN as a hypointense

lesion on proton density and T2*-weighted images was re-

ported in a 14-year-old child with left hemiballismus.49 In

adults, STN involvement was occasionally reported in other

acquired diseases affecting the CNS including ischemic

stroke,50e52 hemorrhages,53 head trauma,54 and neoplastic

lesions.55,56

Finally, a special comment about dentatorubral-

pallidolusyan atrophy (DRPLA, OMIM 125370) is needed.

DRPLA is an autosomal dominant disorder caused by CAG

repeat expansion in the ATN1 gene located on chromosome

12p13.31. Onset in childhood is rare andmost childhood-onset

patients present with ataxia, dementia, progressive myoc-

lonus and epilepsy.57 In adults, typical neuroimaging findings

in DRPLA include atrophic changes in the cerebellum and

brain stem (particularly the pontine tegmentum) and sym-

metric T2- and FLAIR-hyperintense signal abnormalities in

GPs, red nuclei, dentate nuclei and STN.57 The characteristic

neuroimaging findings of the childhood-onset DRPLA are at-

rophy of the cerebellum and pontine tegmentum as well as

T2- and FLAIR-hyperintense signal of the periventricular

white matter, while there is absence of abnormalities

involving the STN.58,59

9. Conclusion

Neuroimaging-based pattern-recognition approach is an

extremely versatile tool in narrowing differential consider-

ations to focus the diagnostic investigation in a wide range of

pediatric neurological diseases. Involvement of the STN on

neuroimaging occurs in few pediatric diseases including LS

due to SURF1 mutation and complex I deficiency, SSADHD,

kernicterus, hepatic encephalopathy in chronic, end-stage

liver failure and acute near total asphyxia in full-term neo-

nates. The consideration of the constellation of clinical history

and findings as well as neuroimaging findings with involve-

ment of certain structures in addition to STN (e.g. basal

ganglia, thalami, brain stem structures, and dentate nuclei)

should allow planning the appropriate diagnostic in-

vestigations to make the correct diagnosis in children with

STN involvement (Table 1).

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