SELECTIVE INJURY OF THE GLOBUS
PALLIDUS IN CHILDREN WITH
POST-CARDIAC SURGERY CHOREIC
d
VNDROME

Choreoathetosis has been recognized as a
complication of cardiac surgery requiring
deep hypothermia and extracorporeal
bypass since a report of brain damage in
10 children treated with these techniques
(Bjork and Hultquist 1960). Choreoathetosis was subsequently reported as a
particular problem after cardiac surgery
for congenital heart defects in both
cyanotic and acyanotic infants and
children (Bergouignan et al. 1961, Delay
et al. 1961, Drew.1961, Brunberg ef al.
1974). Since the early 1960s. deep
hypothermic cardiac arrest (DHCA) has
become a central feature of cardiac
surgery in young patients. It now permits
the cardiac surgeon to carry out definitive
corrective surgery on patients with
congenital heart disease during the first
few weeks of life, with good results in the
great majority (Venugopal et 01. 1973,
Subramanian 1983). Improved techniques
(especially hemodilution during bypass)
and improved filters have greatly reduced
the risk of adverse neurological events,
but postoperative chorea remains a
significant problem, with a reported
incidence of around 1 or 2 per cent since
1980 (Clarkson ef al. 1980, Chaves and
Scaltsas-Persson 1988, Robinson el al.
1988, DeLeon et al. 1990, Kececioglu el
al. 1990, Wical and Tomasi 1990, Wong
ef al. 1992).
The neuropathology of this complication

has been elusive. In the reports cited
above, the picture was complicated by
more widespread neurological and neuropathological changes secondary to emboli
and overt ischemic damage with death in
the early postoperative period. More
recent reports with pathological studies
have been scarce and incomplete (Chaves
and Scaltsas-Persson 1988, Robinson el
al. 1988). We report the clinical and
neuropathological findings in two
patients with cyanotic congenital heart
disease who developed the typical
choreoathetosis syndrome in relative
isolation from other neurological
symptoms and signs. One infant survived
for two weeks after surgery, and the other
survived for four weeks, allowing
assessment of the neuropathology in the
early phase of their illness.
Subjects and method
Clinical records of both infants wcrc
reviewed. Both patients had also been
examined during life by one of the
authors (c.F.B.). Complete postmortem
examinations were performed according
to standard protocols. The brains were
immersion-fixed in buffered 20 per cent
formalin for two weeks, then sectioned
and examined macroscopically. Sections
for microscopic examination were embedded in paraffin wax and stained with
hematoxylin and eosin/Luxol fast blue,

6

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Fig. 2. Case I: medial globus pallidus. Preservation of nerve cells, but loss of myelin
staining and fragmentation of myelin sheaths. Lux01 fast bfue/cresyl violet x 800.

Fig. 3. Case 1: lateral globus pallidus. Scattered hypertrophic astrocytes (arrows) with
visible cytoplasm and cytoplasmic processes. GFAP immunocytochemistry x 660.

137

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138

hypertension of the trunk were noted.
During the subsequent two weeks she
continued to have respiratory distress,
cardiac arrhythmia and fever. It was
noted that she was ‘in constant motion’
when awake, and ‘restless and flailing’
during episodes of SVT. Because of
continuing respiratory distress and rightto-left shunt, she underwent closure of the
ventriculoseptal defect with 75 minutes
cardiac arrest time. Postoperatively she
became increasingly agitated, with nonpurposeful
choreic
and
ballistic
movements that increased on stimulation
and decreased with sleep or heavy
sedation with diazepam and morphine.
She was hypotonic with normal reflexes
and bilateral plantar flexor responses. CT
scan showed ‘diffuse loss of brain mass’
without a focal lesion. She continued to
decline, and died following an episode of
bradycardia one month after the first
operat ion.

Neuropathological examination
Gross examination of the brain showed
mild enlargement of the lateral and third
ventricles, but normal brain weight. On
microscopic examination, the cerebral
neocortex appeared well preserved and
the white matter was appropriately
myelinated. There were rare microscopic
foci of neuronal loss, with mild
rarefaction of neuropil and reactive astrocytosis in the C A I region of the
hippocampus. The putamen and caudate
nucleus appeared well preserved. Rare
calcospherites were seen and some glial
nuclei were vesicular.
There was marked neuronal loss in the
globus pallidus (Fig. 1; and comparison
case, Fig. 9,greater in the lateral than in
the medial segment. Myelin staining was
pale in the globus pallidus, and fragments
of myelin were present in both lateral
(Fig. 1) and medial (Fig. 2) segments.
Macrophages were sparse, but hypertrophic astrocytes and glial fibers could be
seen with immunohistochemical staining
for GFAP (Fig. 3). The lenticular fasciculi,
pallidothalamic fasciculi and subthalamic
nucleus appeared vacuolated and myelin
fragments could also be seen in pallidosubthalamic fiber bundles traversing the
internal capsule.
With GFAP immunostaining, reactive

astrocytes were seen in small numbers in
the neostriatum, including the nucleus
accumbens, the medial thalamus and the
hypothalamus, and were interdigitated
among the fibers of the lenticular
fasciculus and posterior limb of the
internal capsule. Brainstem, cerebellum
and spinal cord were well preserved except
for the cerebellar dentate nucleus, which
contained scattered acutely necrotic
neurons with hypereosinophilic cytoplasm
and pyknotic nuclei.
CASE2
This 2%-year-old boy was born after
an uncomplicated term pregnancy and
delivery weighing 2700g. Cyanosis and
heart murmur noted at nine weeks of age
led to a diagnosis of tetralogy of Fallot
with pulmonary atresia and multiple
systemic-to-pulmonary collateral vessels.
He was admitted to hospital because of
pneumonia at six and 19 months of age.
He walked alone at 18 months, and by the
time of admission to the Children’s
Hospital at 2% years he was speaking in
three- to five-word phrases with a
vocabulary of approximately 100 words.
Following repeat cardiac catheterization, hypothermic cardiopulmonary
bypass surgery was performed, with
placement of an aortic homograft
between the right ventricular outflow
tract and the hypoplastic left and right
pulmonary artery junction site. Cardiac
bypass time was 112 minutes, with 29
minutes of circulatory arrest. Intraoperative esophageal and tympanic
temperatures were 12 and 15”c,
respectively, and the hematocrit was
maintained at 22 to 26 per cent. Postoperatively he was lethargic but arousable,
with normal movement of the extremities.
Sedation was instituted on postoperative day two, to control ‘thrashing’
movements. Four days postoperatively he
developed abnormal jaw movements and
tongue thrusting, followed by increasing
ballistic and choreiform movements of
the extremities, which were fully evolved
by postoperative day six. He was
hypotonic, with reduced reflexes but
normal plantar responses, and developed
episodes of conjugate upward deviations
of the eyes lasting approximately 30
seconds. CT scan showed a parietal lesion

Fig. 4. Case 2: lateral globus pallidus. Loss of nerve cells and myelin fragmentation similar
to that seen in case I . I.uxol fast blue/cresyl violet x800.

Fig. 5. Comparison case (34-monrh-old boy with gastro-intestinal lymphangiectasia and no
hktory of neurological disease): lateral globus pallidus with normal density of nerve cells
and myelin staining. Lux01 fast blue/cresyl violet x 800.

139

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consistent with old infarct. The abnormal
movements persisted except during sleep,
despite therapy with carbamazepine,
haloperidol and chlorazepam. They were
diminished by deep sedation with
lorazepam and chloral hydrate. Atrial
dysrhythmias developed 15 days postoperatively, and on the next dayfollowing an episode of vomiting and
cyanosis-he developed cardiorespiratory
arrest and died.

Neuropathological examination
Grossly, the brain was normal in weight.
On microscopic examination, there was a
small cavitated old infarct in the left
inferior parietal lobule, which involved
the cortex and subcortical arcuate fibers,
but did not extend into the deeper parietal
white matter. Wallerian degeneration was
found in the white matter underlying the
infarct. No evidence of thrombus or
embolus was identified. The caudate
nucleus, putamen, subthalamic nucleus,
thalamus and hippocampus appeared well
preserved, except for the presence of a
small number of scattered calcospherites
in the neostriatum.
There was neuronal loss in the globus
pallidus, chiefly in the lateral segment
(Fig. 4; and comparison case, Fig. 5 ) .
Myelin staining was also diffusely
decreased (though less markedly than in
the previous case), and myelin fragments
were present. Reactive astrocytes were less
prominent than in case 1. With GFAP
immunostaining, small numbers of
reactive astrocytes were seen in the
centrum semiovale and the corpus
callosum on the side of the infarct, and
also focally in the dorsomedial nucleus of
the thalamus and the medial hypothalamus. A few vacuoles and axonal
spheroids were seen in the central
tegmental tract of the pons. The
brainstem, cerebellum and spinal cord
otherwise appeared well preserved.

Discussion

I40

The most prominent neuropathological
abnormality in these two young patients
with choreoathetosis subsequent to
cardiac surgery with DHCA involved the
external globus pallidus and consisted
primarily of loss of neurons, nerve fiber
degeneration and gliosis. The localization

was consistent with current concepts of
clinical correlation (Mitchell et ul. 1989),
but the pathological changes were subtle
and did not indicate the pathogenesis of
the lesion. The lack of frank necrosis and
vascular change argues against the
concept of microcirculatory ‘no-reflow’,
embolic infarction and severe generalized
anoxic-ischemic injury. The localization
implies a special vulnerability of the
globus pallidus to some aspect of the
operation. Ferry’s (1990) review of
neurological complications from a survey
of six cardiac surgery centers also
suggested that there was a management
variable, in that only three of the six
centers reported postoperative chorea.
Though the first report of chorea
following cardiopulmonary bypass and
DHCA appeared in 1960, and noted the
presence of injury to the globus pallidus,
the pathological findings also included
widespread abnormalities reflecting overt
ischemia or regional circulatory failure
(Bjork and Hultquist 1960). Few subsequent early reports included neuropathological findings. The employment of
hemodilution during bypass, improved
filters and other technical advances have
greatly reduced embolic and overt
ischemic brain damage and lowered the
earlier prohibitive mortality rate from
DHCA (Mayer 1991). Nevertheless, since
1988 six publications (Robinson el al.
1988, DeLeon et al. 1990, Kececioglu et
al. 1990, Wical and Tomasi 1990, Wong
et al. 1992, Huntley et al. 1993) and two
abstracts (Chaves and Scaltsas-Persson
1988, Medlock et al. 1992) have indicated
that the complication of this movement
disorder has persisted. However, these
reports have given details of only two
cases with pathology studies. Among the
five children with choreic syndrome
reported by Robinson et al. (1988), no
brain abnormalities ‘in addition to those
of Down’s syndrome’ were seen in one
autopsied child with Down syndrome and
tetralogy of Fallot who died five months
postoperatively and had recovered from a
choreic syndrome approximately one
month before death. One autopsied case
from the four children reported by
Chaves and Scaltsas-Persson (1988)
showed ‘hypoxic neuronal degeneration
and capillary proliferation in the basal

ganglia’, but further details are not
available.
The postoperative chorea syndrome
seen in these children appears to be
primarily a complication of cardiopulmonary bypass with hypothermia,
with the added risk factor of induced
cardiac arrest in the majority of patients.
The central feature of the clinical
syndrome is a movement disorder consisting of chorea or ballismus, oculomotor
abnormality and hypotonia, characteristically arising after an asymptomatic
latent period of one to seven days. Most
of the severely affected patients who
survive have also had significant mild-tomoderate cognitive abnormalities.
Among all the similar clinicopathological
disorders that may provide some insight
into the problem, perhaps the closest is
the choreoathetosis reported by Perlman
and Volpe (1989) in preterm infants with
bronchopuimonary dysplasia. An identical
movement disorder appeared at about
three months of age. These seriously ill
infants required continuous treatment
using a ventilator and oxygen. Neuropathology study was available for one
infant, who showed a ‘moderate degree Qf
neuronal loss with astrocytosis in caudate,
putamen, globus pallidus and thalamus’.
The authors hypothesized that chronic
hypoxia was a likely cause, as in these
infants the deficient oxygenation was not
acute but chronic.
The mechanism for the pallidal damage
in the setting of DHCA remains uncertain.
Neuropathology studies in both adults
and children treated with cardiopulmonary
bypass have demonstrated a variety of
brain lesions, including thrombo-embolic
infarctions, diffuse or segmental necrosis
in the cerebral cortex (especially calcarine
cortex), hippocampus and medial globus
pallidus, and focal or diffuse white matter
necrosis, especially in young infants
(Aguilar et al. 1971, Terplan 1976,
Bozdky ef al. 1984). Lack of tissue
necrosis in the pallidum and relative
sparing of other brain regions such as the
hippocampus, usually regarded as highly
susceptible to hypoxic-ischemic damage,
suggest either that hypothermia significantly ameliorates the tissue reaction to
such damage or that a mechanism other
than hypoxia-ischemia is responsible.

The clinical data indicate that the age of
the patient is an important factor. The
literature and our own experience indicate
that infants tend not to be vulnerable
during the first four to six weeks of life,
and that up to 10 or 12 months chorea is
likely to be mild and usually reversible.
The syndrome primarily affects older
infants and children to mid-childhood,
and has seldom been reported in adults
(Egerton ef al. 1963). In this context, the
finding of Chugani ef d.(1987) that the
metabolic rate for glucose in humans
between three and nine years was significantly higher than values in infants and
adults in all regions of the brain including
the lenticular nucleus may be important.
Positron emission tomography, however,
did not permit separate analysis of the
globus pallidus. Also of possible
relevance is the interesting observation
that there is transient glutaminergic
innervation in the rat globus pallidus in
early life that is several times greater than
values at birth or in the adult, with a peak
on the seventh postnatal day (Greenmyre
el al. 1987). The data suggest that there
are high values in two- and six-week-old
infants, but no developmental time course
was reported.
The consistent risk factors during
surgery are hypothermia and cardiopulmonary bypass. In the majority of the
reported patients, and in almost all of
those admitted to the Boston Children’s
Hospital (Wong ef al. 1992), another
factor has been the total circulatory arrest
that is carried out to obtain a bloodless
field during a critical phase of the
operation. These risk factors are all
consistent with the hypothesis that the
injury to the globus pallidus is anoxicischemic in origin, and that complete
tissue necrosis is prevented by hypothermia. Nevertheless, it is clear that
additional factors are required because
the complication only occurs in one or
two per cent of patients, and duration of
bypass, duration of cardiac arrest and
depth of hypothermia have not proved to
distinguish between affected and unaffected patients.
The anecdotal report of Drew (196l),
that slowing the rate of cooling made a
significant difference in incidence, has not
been confirmed or denied by systematic

f
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141

study. However, it is clear in our own
studies of 13 patients at Boston Children’s
Hospital with severe choreoathetosis that
some developed the disorder even though
the duration of cooling time was extended
to up to an hour (Wong et al. 1992). We
also found marginally significant differences in the cooling time to cardiac arrest,
and slightly more significant variation in
cooling and warming rates, as well as in
depth of cooling between patients with
and without chorea. While the hypothesis
that ‘cold shock’ is solely responsible has
not stood the test of time, rapid cooling
has nevertheless been shown expcrimentally to lead to very uneven rates of
cooling in the body and brain of dogs
(Almond et al. 1964). A role for alterations
in regional cerebral blood flow was
suggested b y A o y a g i et a/. (1975). who
noted a significant reduction in blood
flow to the globus pallidus during rewarming after hypothermia in infant
baboons. Greeley et al. (1989) measured
cerebral blood flow with xenon clearance
techniques in infants and children
undergoing deep hypothermic cardiopulmonary bypass (with or without total
circulatory arrest) and found decreased
cerebral blood flow because of temperature reduction with loss of cerebral
pressure-flow autoregulation. They also
noted impairment of cerebral reperfusion
in the patients who had also been
subjected to total circulatory arrest with
‘alpha-stat’ management (see below).
Perhaps more significant are the preoperative reduction of pulmonary collateral vessels, which may steal blood
from the brain especially during the

cooling and re-warming period (Wong ef
al. 1992), and the management of COZ
and PH during the bypass (‘alpha stat’ vs
‘PH stat’) (Wong et a!. 1992, Jonas et a/.
1993). The change from ‘pH stat’
management (in which coz is added to
the perfusion mixture) to ‘alpha stat’ (in
which it is not) has been associated with a
noticeable increase in postoperative
chorea and a worsened developmental
outcome in infants (Wong el 01. 1992).
The increased level of Coz of the pH
stat management presumably increases
cerebral blood flow during bypass and
could be a significant factor in the
pathogenesis of brain damage.
Neither the pathology nor the clinical
data currently provide an answer to this
problem, which probably centers around
the several f a c t o r s t h a t m a y lead t o partial

ischemia. There will have to be further
studies of these factors and of the
vulnerability of the pallidum in the setting
of hypot hermic cardiopulmonary bypass.
Accepted for publication 121h May 1994.
Acknowledgements

The authors wish to thank Mr Benjamin True 111 of
Medical Photography, Harper Hospital, for
producing the figures and Miss Laura F. Kuleva for
help with the manuscript. This paper was presented
in part at the 1991 Annual Meeting of the American
Association of Neuropathologists in Baltimore,
MD.
Authors ’ Appointments
*William J. Kupsky, MD;
Monica A. Drozd. RA;

Charles F. Barlow, MD;
Departments of Pathology and Neurology,
Children’s Hospital and Harvard Medical School,
Boston, MA.
*Corr?spondence to first author at Department of
Pathology, Harper Hospital, 3990 John R . . Detroit,
MI 48230, USA.

SUMMARY
Occasionally children undergoing cardiac surgery using cardiopulmonary bypass with deep
hypothermia and cardiac arrest develop a postoperative syndrome of acute chorea. The authors
report the neuropathological findings in two such children surgically treated for congenital heart
disease. Examination of the brain showed neuronal loss, reactive astrocytosis and degeneration of
myelinated fibers (without frank necrosis) in the globus pallidus, primarily the outer segment, with
sparing of other regions commonly susceptible to hypoxic-ischemic necrosis. The localization and
relative mildness of the brain damage suggest a susceptibility of the globus pallidus to injury in this
setting and implicate disruption of pallidal pathways in the pathogenesis of post-cardiac surgery
choreic syndrome.

R~SUME
A tteinte selective du noyau lenticulaire chez I’enjant. dons les syndromes choreiques suivant une
chirurgie cardiaque
11 arrive que des enfants subissant une chirurgie cardiaque pour shunt cardiopulmonaire, et

142

presentant une hypothermie profonde et un arrit cardiaque, presentent un syndrome choreique aigu
post-operatoire. Les auteurs rapportent les donnees neuropathologiques chez deux enfants traites
pour malformation cardiaque congknitale. L’examen du cerveau revkla une perte neuronique, une

reaction astrocytaire et une degenirescence des fibres myelinisees (sans necrose franche) dans le
noyau lenticulaire, principalement la partie externe, les autres regions pouvant communement
souffrir d’une necrose hypoxique-ischemique etant cpargnees. La localisation et la relative
moderation du dommage cerebral suggerent une susceptibilite du noyau lenticulaire aux lesions et
une interruption des voies lenticulaires dans la pathogenie du syndrome choreique survenant apres
une chirurgie cardiaque.

p’

m
n
o\

0‘

ZUSAMMENFASSUNG
Selektive Globus pallidus Verletzung bei Kindern rnit Chorea Syndrom nach Herzoperation

Nach einer Herzoperation mit Herz-Lungenmaschine. Hypothermie und Herzstillstand entwickeln
Kinder gelegentlich postoperativ ein akutes Chorea Syndrom. Die Autoren berichten iiber die
neuropathologischen Befunde bei zwei solcher Kinder, die wegen eines kongenitalen Herzfehlers
operiert worden waren. Die Untersuchung des Gehirns ergab Verlust von Neuronen, reaktive
Astrozytose und Degeneration der myelinisierten Fasern (ohne freie Nekrose) im Globus pallidus,
hauptsachlich im aufieren Segment, wobei die anderen Kegionen, die gewohnlich fur hypoxischischamische Nekrosen anfallig sind, ausgespart blieben. Die Lokalisation und die relative
Geringfugigkeit des Hirnschadens lassen eine Anfalligkeit des Globus pallidus fur Schadigungen
dieser Art vermuten und haben eine Unterbrechung der Bahnen des Pallidums als Ursache des
Chorea Syndroms nach Herzoperation zur Folge.

c

E
.-

A
L

RESUMEN
Lesidn selecfiva del globus palidus en niitos con sindrome coreica posr cirugia cardiaca

Ocasionalmente nillos a 10s que se les ha practicado una cirugia cardiaca utilizando un by-pass
cardiopulmonar con hipotermia profunda y par0 cardiac0 sufren un sindrome postoperatorio de
corea aguda. Los autores aportan 10s hallazgos neuropatolbgicos en dos casos asi tratados por
padecer una enfermedad cardiaca congenita. El examen del cerebro mostro perdida neuronal,
astrocitosis reactiva, y degeneracion de fibras mielinizadas (sin franca necrosis en el globus palidus)
sobre todo del segment0 externo, con indemnidad de otras regiones comunmente susceptibles a la
necrosis hypoxica-isquirnica. La locali7acion y relativa poca importancia de la lesion cerebral sugiere
una susceptibilidad del globus palidus a la lesion e implica una disrupcion de las vias palidales en la
patogenia del sindrome coreico post cirugia cardiaca
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