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of Child Neurology

Possible Mechanisms in Infants for Selective Basal Ganglia Damage From Asphyxia, Kernicterus,
or Mitochondrial Encephalopathies
Michael V. Johnston and Alexander H. Hoon, JR
J Child Neurol 2000 15: 588
DOI: 10.1177/088307380001500904
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Original Article

Possible Mechanisms in Infants for Selective
Basal Ganglia Damage From Asphyxia,
Kernicterus, or Mitochondrial Encephalopathies
Michael V. Johnston, MD; Alexander H. Hoon Jr, MD

ABSTRACT

Magnetic resonance imaging and neuropathologic studies have demonstrated remarkably selective patterns of injury to
subregions of the basal ganglia in children. Examples are kernicterus and certain mitochondrial encephalopathies, which
cause selective injury to the globus pallidus, and near-total perinatal asphyxia, which causes lesions in the putamen and
thalamus. To explain the differential vulnerability of nuclei within millimeters of each other, we hypothesize that their
locations within the neurotransmitter-specific circuitry of the basal ganglia motor loop are important. In severe hypoxicischemic encephalopathy, excitatory glutamatergic pathways into the putamen and thalamus are overactive, but the globus
pallidus might be protected because its activity is silenced by inhibitory neuronal activity. In contrast, the relatively high
resting neuronal activity in the globus pallidus might make it more vulnerable to less intense, subacute oxidative stresses
from mitochondrial toxins such as bilirubin or from genetic mitochondrial disorders. This hypothesis has implications for
designing neuroprotective therapies and for treating associated chronic movement disorders. (J Child Neurol
2000;15:588-591).

Brain magnetic resonance imaging (MRI) in children with
neurologic disorders can demonstrate remarkably selective patterns of injury in the basal ganglia. Recent reports
have shown a pattern of selective damage in the putamen
and thalamus following near-total peripartum asphyxia in

We present three infants with selective basal ganglia lesions
and consider the pathogenesis of their motor disability.

term infants, sparing the globus pallidus, which lies directly

Case 1: Globus Pallidus Injury Secondary

medial to the putamen.2-6 In sharp contrast, kemicterus
from hyperbilirubinemia or damage from cardiac surgery in
children often targets the globus pallidus while sparing the
putamen and thalamus. 7,1 Other genetic metabolic disorders that target the basal ganglia in infants, such as mitochondrial encephalopathies, glutaric aciduria and propionic
aciduria, can variably and selectively damage regions of
the basal ganglia depending on the nature of the insult.9-11
These patterns of selective basal ganglia injury could provide insight into the mechanisms of injury as well as the
pathophysiology of the movement disorders they cause.

CASE REPORTS

to Pyruvate Dehydrogenase Deficiency

A 21-month-old boy was evaluated for episodic lethargy, choreo-

athetosis, and weakness. His development was reportedly normal
until 6 months of age, when he had delay in psychomotor milestones

with episodic weakness associated with viral illness. Metabolic test-

ing revealed lactic acidosis exacerbated by feedings and improved
with fasting. Brain MRI showed selective, hyperintense signal
abnormalities in the globus pallidus bilaterally (Figure 1A). The diagnosis of pyruvate dehydrogenase deficiency was established by
enzymatic assay in cultured skin fibroblasts. This patient’s MRI has
been published previously’1
Case 2: Kernicterus
An 8-month-old girl was referred for hypotonia and hearing loss.

Received Nov 17, 1999. Accepted for publication Jan 26, 2000.

Following a pregnancy complicated by oligohydramnios, she was

From the Division of Neurology and Developmental Medicine, Kennedy
Krieger Institute and Johns Hopkins University School of Medicine,
Baltimore, MD.

born by vaginal delivery at 36 weeks’ gestation. Following dis-

Address correspondence to Dr Michael V. Johnston, Room 610, Kennedy
Krieger Institute, 707 North Broadway, Baltimore, MD 21205. Tel: 410-5029492; fax: 410-502-9524; e-mail: johnston@kennedykrieger.org.

charge at 36 hours of life, she developed lethargy and poor feeding and was readmitted to the hospital with a total bilirubin level
of 28 mg/dL and encephalopathy, including seizures, hypotonia, and
poor suck. On examination at age 8 months, she had microcephaly,

588
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589

limitation of upgaze, tongue thrusting, and hypotonia A T2 weighted
brain MRI showed hyperintense signal in the globus pallidus bilaterally and delayed myelination, but the thalamus and other basal

ganglia structures were normal (Figure 1B). Evaluation included
normal plasma amino acids and urine organic acids and brainstem auditory evoked responses consistent with an auditory

neuropathy.
Case 3: Near-Total Asphyxia with

Hypoxic-Ischemic Encephalopathy
Pregnancy was uncomplicated until an acute umbilical cord prolapse necessitated an emergency cesarean section delivery at term.
The patient was resuscitated in the delivery room and taken to the
neonatal intensive care unit, where seizures developed during the
first 24 hours of life. On neurologic examination during the first
week of life he was severely hypotonic with hypoactive reflexes
and an absent gag reflex; assisted ventilation was required for 9 days.
On day 6 of life, an MRI of the brain showed hyperintense signal
in the caudate and putamen bilaterally on a Tl-weighted sequence.
At 4 months of age, he had truncal hypotonia and dystonic posturing
of his hands. At I year of age, an MRI showed that the enhanced
signal on the T,-weighted sequence had disappeared, but there
was hyperintensity in the posterior segments of the putamen and
in the thalami bilaterally (Figure 1C). The globi pallidi were normal. At 2 years of age he is severely disabled with extrapyramidal
cerebral palsy manifested by axial hypotonia, rigidity, dystonic
posturing of the arms and hands, and inability to vocalize or
swallow.

DISCUSSION

These three cases, chosen from numerous others in our
Movement Disorders Program, illustrate injury to specific
basal ganglia nuclei in infants visualized using brain MRI.
Similar patterns of injury have been documented in the literature and are seen clinically on a regular basis.1-7 They

demonstrate that the pattern of basal ganglia injury in
infants can be quite focal despite the fact that the entire brain
is exposed to a metabolic disorder. They illustrate two
sharply contrasting patterns of injury: selective pallidal
injury associated with disorders such as kernicterus or certain mitochondrial disorders versus the putamenal and thalamic injury pattern associated with severe asphyxia. It is
noteworthy that the contrast between these two patterns of
injury, which have been visualized only recently with MRI
in living children, was previously described in neuropathologic material by Ahdab-Barmada and Moosy in

1984.12
Given the close proximity of these neuronal nuclei
within the basal ganglia, it seems likely that their selective
vulnerability is based on differences in their intrinsic vulnerability to metabolic stressors rather than to differences
in blood flow or energy delivery. One factor that can strongly
influence the vulnerability of neurons is their position within
excitatory neuronal circuits The relative positions of the
putamen, globus pallidus, and thalamus in the circuitry of
the basal ganglia are shown schematically in Figure 2. Current concepts of how the basal ganglia control movement
focus on the flow of information through a multineuronal
feedback loop from frontal cortex down to the putamen,
inward through the globus pallidus to the thalamus, and back
up to the cortex. 14 The inhibitory influence of the globus pallidus on the thalamus and thalamocortical projections is
thought to be a key step in controlling movement. The
globus pallidus indirectly controls frontal cortical activity
by influencing the activity of thalamocortical projections.
If neuronal activity in the pallidal projections to the thalamus is high, movement will cease because frontal lobe
activity directed by the thalamus is silenced. However, if pallidal inhibition is reduced, the thalamus is disinhibited and
enhances frontal lobe activation of volitional movement.
Although the cerebral cortex, putamen, globus pallidus

Figure 1. A, MRI from child with pyruvate dehydrogenase deficiency who had episodes of dystonia and athetosis. Note hyperintense lesions
in globus pallidus bilaterally (arrows). Rest of basal ganglia and thalamus are normal. B, Child with kernicterus. Note increased signal in globus
pallidus (arrows); rest of basal ganglia and thalamus is normal.There is also delayed myelination. C, Child following severe asphyxia. Note
increased signal in thalamus and putamen bilaterally (arrows).

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590

tex, supporting this hypothesis. 19 Hyperexcitability in these

Figure 2. Diagram of normal basal ganglia motor control circuit and
areas damaged by near-total asphyxia. Arrows indicate synapses with
excitatory glutamate neurotransmitter; blunted lines indicate inhibitory
y-aminobutyric acidergic (GABAergic) inhibitory synapses. The loop
connecting frontal cortex, putamen, globus pallidus interna (GPi),
and thalamus is the direct pathway; globus pallidus externa (GPe) and
subthalamic nucleus (STN) are in the indirect pathway. Movement is
controlled by activity in the cortex. Neonatal globus pallidus also has
transiently stronger innervation by glutamate fibers that is not prominent in the adult. Shaded areas indicate regions targeted by asphyxia.
Each region receives strong excitatory glutamate innervation. Note that
if these regions are firing rapidly, the effect on globus pallidus interna
and globus pallidus externa is expected to be inhibitory because of
inhibitory input from putamen. Residual effects of this damage include
rigidity; paucity of movement, especially in upper extremities; and
paucity of speech.

interna, and thalamus are linked together in a continuous
multisynaptic loop, the synaptic neurotransmitter relationships distinguish the pallidum from the other three

components (Figure 2). When the cortex, putamen, and
thalamus are being activated by strong glutamate excitatory
inputs, the pallidum is inhibited. In contrast, when the pallidum is active, the thalamus, motor cortex, and putamen
are silenced by its y-aminobutyric acid (GABA)-ergic
inhibitory influences.
The reciprocal synaptic relationships among these
regions under physiologic conditions could influence vulnerability of the pallidum versus the putamen and thalamus
in pathologic circumstances. In asphyxia, brain regions that
receive strong glutamate innervations are vulnerable to
injury because of the accumulation of high levels of synaptic glutamate that occurs when reuptake pumps suffer
energy failure15,16 (Figure 2). Accumulation of glutamate
might be especially sensitive to failure of glycolysis, which
is very important for powering glial glutamate reuptake

circuits could be directly related to excitotoxic lesions in
thalamus and putamen seen on MRI following asphyxia. 20,21
However, the position of the globus pallidus in the multisynaptic loop could reduce its vulnerability to injury. When
seizure activity convulses the cortex and its projection sites,
one would predict that the globus pallidus would be strongly
inhibited and relatively protected (Figure 2).
A disorder of energy metabolism is also thought to
mediate the damage from kernicterus and certain mitochondrial disorders, but the nature of the energy deficiency
is likely to be different from that seen in near-total asphyxia22
(Figure 3). Kernicterus can result from the toxic effect of
bilirubin disrupting mitochondrial metabolism.7 Both kernicterus and pyruvate dehydrogenase deficiency can injure
neurons primarily by inhibiting mitochondrial maintenance
of membrane potentials. In contrast to acute severe asphyxia,
glycolysis is unimpaired in mitochondrial oxidative phosphorylation disorders and is usually markedly enhanced, as
reflected by elevated lactate levels. In mitochondrial disorders, there is often a ready supply of glucose, which is not
limited as it is in ischemia associated with severe asphyxia.
Disorders of mitochondrial metabolism have been proposed
to injure neurons through a process of subacute &dquo;passive
excitotoxicity&dquo; when membrane depolarization leads to
opening of postsynaptic voltage-dependent N-methyl-Daspartate (NMDA) glutamate and sodium channels.23 The relatively high baseline firing rate of pallidal neurons, which
are disinhibited when the rest of the motor system is quiet,
could predispose them to injury from mitochondrial failure.24
Postmortem studies of human infants also indicate that the
immature globus pallidus has a relatively high density of
glutamate receptors that is lacking in adults.25 Immature
rodents also have been shown to have a transient glutamate

plumps. 17 Hypoxic-ischemic encephalopathy following severe
asphyxia is characterized by seizures and electrical excitability seen on electroencephalography, suggesting that the
corticothalamic, thalamocortical, and corticoputaminal
excitatory projections are active Positron emission tomographic (PET) studies of human infants with hypoxicischemic encephalopathy after severe asphyxia have shown
hypermetabolism in the basal ganglia and perirolandic cor-

Pattern of injury with kernicterus and some mitochondrial disorders such as pyruvate dehydrogenase deficiency. Kernicterus
targets globus pallidus and subthalamic nucleus. Net effect is to disinhibit thalamus, producing a hyperkinetic movement disorder. GPi
globus pallidus interna; STN subthalamic nucleus; GPe globus

Figure 3.

=

pallidus externa.

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=

=

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innervation in the globus pallidus that regresses in adults. 15
This novel excitatory circuitry in the infant basal ganglia,
which could originate from the subthalamic nucleus, might
contribute to the vulnerability of the globus pallidus to
oxidative stress. As shown in Figures 2 and 3, the subthalamic nucleus is likely to be active at rest but silenced in

asphyxia.
According to this hypothesis, the selective vulnerability of the globus pallidus versus the putamen, thalamus, and
cortex is determined by their positions within the neuronal
circuitry of the basal ganglia, their electrical activity, and their
intrinsic vulnerability. A severe insult from asphyxia might
spare the globus pallidus by silencing it. However, it remains
relatively vulnerable to subacute energy failure of oxidative
metabolism in mitochondrial disorders. Cases of combined
energy failure, such as hypoglycemia superimposed on an
oxidative phosphorylation disorder, might lead to the more
severe combined putamenal and pallidal lesion that is sometimes seen clinically.
The neuronal circuit relationships in the basal ganglia
also might help to explain the neurologic disability associated with each type of lesion. The putamenal/thalamocorti-

cal lesion following asphyxia disrupts integral components
of the circuit involved in motor activation, producing a
reduction in movements; rigidity, especially in the upper
extremities; and reduced speech production later on. Some
of the bradykinesia in these patients could relate in part to
enhanced activity in the relatively intact globus pallidus
(Figure 2). In contrast, loss of neurons in the globus pallidus
leads to disinhibition of the thalamocortical projections,
leading to the hyperkinetic choreoathetoid movements typical of kemicterus. Dystonia can arise in either group of
patients as a result of a disrupted pattern of pallidal activ-

ity24
~.Y
(Figure 3).
These observations in children with acquired basal
ganglia injuries suggest that there is a plausible relationship
between physiologic circuitry in the motor loop of the basal
ganglia, mechanisms of injury, the location of selective
lesions seen on MRI scanning, and neuropathology and the
pattern of neurologic disability. New physiologic studies in
experimental models indicate a strong link between activity of glutamate synapses, glucose metabolic rate determined through PET scanning, and activation of regional
cerebral blood flow assessed by functional MRI. 19>26 These
techniques might be useful for testing these hypotheses in
infants and children with syndromes that cause patterns of
selective neuronal vulnerability in the basal ganglia.

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Ahdab-Barmada M, Moosy J: The neuropathology of kernicterus
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Olney JW, Collins RC, Sloviter RS: Excitotoxic mechanisms of
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Hoon AH, Reinhardt EM, Kelley RI, et al: Brain magnetic resonance
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Silverstein FS, Buchanan K, Johnston MV: Perinatal hypoxiaischemia disrupts high affinity [3H]-glutamate uptake into synaptosomes. J Neurochem 1986;47:1614-1619.

Magistretti PJ, Pellerin L, Rothman DL, Shulman RG: Energy on
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