Evolving Understanding of

Hypoxic-Ischemic Encephalopathy in the Term Infant

Linda S. de Vries, MD, PhD,* and Frances M. Cowan, MRCPCH, PhD†

Our aim was to document changes in the evaluation and prognosis of term-born infants
with neonatal encephalopathy of hypoxic-ischemic origin, with particular reference to our
own experiences and influences, and to summarize the debate on causation and the relative
importance of antenatal and perinatal factors. High quality neonatal cranial ultrasound and
magnetic resonance imaging and spectroscopy have enabled the accurate early visualiza-
tion of different patterns of hypoxic-ischemic brain injury and prediction of their associated
outcomes. Long-term follow-up shows that cognitive and memory difficulties may follow
even in children without motor deficits. The very early use of electrophysiologic methods
has allowed broad prognostic categorization of infants when this is not possible from
clinical assessment or imaging, providing a rationale for entry into intervention trials, such
as therapeutic hypothermia. This work has also shown that most of these infants have
evidence of acute hypoxic-ischemic brain injury that explains their symptoms and
outcomes.
Semin Pediatr Neurol 16:216-225 © 2009 Published by Elsevier Inc.

A lthough there are many papers in the early and mid 20th
century discussing the pathophysiological mechanisms
of what was commonly termed “birth asphyxia,” there are a
few describing the clinical examination of affected infants
and none that describe investigations that help either to con-
firm the diagnosis or to predict outcome. Even in the early
1980s, the assessment of full-term infants with neonatal en-
cephalopathy (NE) after “birth asphyxia” was limited to neu-
rologic examination and preliminary electroencephalogram
(EEG) studies and prognosis was discussed only in very
broad terms.1 Later in the decade, bedside cranial ultrasound
started to be used, and during this period the concept of
multidisciplinary neonatal neurology was first introduced to
the neonatal intensive care unit of the Hammersmith Hospi-
tal by Professors Victor and Lilly Dubowitz. The neurologic
assessment was based on the work from Sarnat and Sarnat2
who had published their staging classification for NE on the
basis of only 21 infants, several years earlier. Lilly Dubowitz
developed her own neurologic assessment using items from
*Department of Neonatology, Wilhelmina Children’s Hospital, UMC, Utre-
cht, The Netherlands.
†Department of Paediatrics and Imaging Sciences, Imperial College, Com-
prehensive Biomedical Research Centre, London, United Kingdom.
Address reprint requests to Frances M. Cowan, MRCPCH, PhD, Department
of Paediatrics, 5th Floor Hammersmith House, Hammersmith Hospital,
DuCane Rd, London W12 HS, United Kingdom. E-mail: f.cowan@
imperial.ac.uk
Amiel-Tison3 and Brazelton,4 that could be performed
quickly even in very sick infants in the incubator and re-
corded on a simple proforma by circling the appropriate
image for each item examined.5 More recently, this examina-
tion has been assessed in a large population of well newborn
term infants, and an optimality score has been developed that
is applicable to the first few postnatal days.6 The predictive
value of the examination at different neonatal postnatal ages
in encephalopathic infants has been also assessed.7
The Sarnat classification2 for documenting the severity of
NE and, from that, predicting outcome was more reliable in
the past as compared to now, because the infant’s clinical
state was less often affected by artificial ventilation and in-
fants were given fewer drugs with a sedative effect. At this
time, continuous amplitude-integrated electroencephalo-
gram (aEEG) monitoring was only just starting in Sweden
and was not generally available.8 Although overt clinical sei-
zures were treated, subclinical seizures mostly remained un-
diagnosed.
Although cerebral ultrasound was being introduced, it was
mainly used in the preterm infant. Imaging was still relatively
limited by narrow fields of view and poor tissue penetration
in the term infant, and its role in detecting injury and pre-
dicting outcome was not quickly established. However, sev-
eral groups reported positive findings as early as 1983.9 An
emphasis on the importance of echogenicity in the central
gray matter was reported a few years later,10,11 noting that this
echogenicity takes time to develop (48-72 h) postnatally un-

216 1071-9091/09/$-see front matter © 2009 Published by Elsevier Inc.

doi:10.1016/j.spen.2009.09.001
Evolving understanding of HIE
less the lesions are hemorrhagic in nature, in which case
echogenicity is seen almost immediately.11
Magnetic resonance imaging (MRI) was being introduced
to the Hammersmith Hospital during the same period by
Graeme Bydder12 and he, together with Lilly Dubowitz and
Jackie Pennock, undertook the first pediatric and then neo-
natal magnetic resonance (MR) scanning. They realized the
importance of neonatal specific coils and sequences for opti-
mal neonatal imaging and also the preparation and supervi-
sion needed to put an infant safely in an MR scanner. It was
soon possible to perform single-slice MRI in our NE popula-
tion, though usually not when infants were still ventilated or
in the first postnatal week. The normal features of the neo-
natal brain as well as patterns of brain injury were recog-
nized. Lesions in the basal ganglia and thalami (BGT) were
better visualized with an inversion recovery sequence than
with computed tomography (CT) scanning, and mild to se-
vere white matter lesions, such as encephalomalacia, were
also recognized (Fig 1).
Besides neuroimaging, there was also an interest in neuro-
physiology. Continuous EEG was introduced and a 2-chan-
nel EEG system became available; however, rather than im-
mediate analysis of the recording, as is nowadays possible
using pattern recognition on a single or 2-channel aEEG,
analysis of the recording would be performed later away from
the bedside, and thus longer term EEG recording was not an
immediate clinical tool.13 Additional information was ob-
tained with visual evoked potentials (EPs), and subsequently
somatosensory EPs were noted to be useful by the team led by
Professor Paul Casaer in Leuven and colleagues.14 Using all
these techniques [neurologic assessment, neuro-imaging
(cranial ultrasound and MRI) and neurophysiology (EEG and
EPs)] simultaneously, the concept of “an integrated ap-
proach” to neonatal neurology was introduced, which led us
to begin recognizing and understanding better the different
patterns of injury seen in encephalopathic infants, which
were not dissimilar from those described in the primate stud-
ies of Myers15 in the mid-1970s.
Figure 1 Neuro-imaging in 1994 of a full-term infant with “acute
near total asphyxia.” Transverse computed tomography (A) and
magnetic resonance imaging (MRI), inversion recovery (IR) se-
quence (B). Abnormalities in the basal ganglia are seen only with
MRI, as areas of increased signal intensity.
217
Around this time, Professor Kenneth Cross at the London
Hospital was investigating the regulation of cerebral blood
flow in newborn infants using strain-gauge plethysmogra-
phy.16 Although this technique was not readily applicable by
the bedside in sick infants, a comparison was made between
the plethysmographic method and Doppler blood flow ve-
locity measurements, which were also being introduced into
neonatal assessment.17 Using Doppler, it was possible to do
repeated bedside measurements. It was found that in asphyx-
iated infants, velocity recordings were often normal on the
first day but became abnormal for the next few days in infants
with poor outcomes.18 This was one of the observations that
led to the concept of a “window of opportunity” before per-
manent damage was established in NE of hypoxic-ischemic
origin.
Concurrently, in the 1980s, Professor Osmund Reynolds
at University College London led a team who were develop-
ing the use of phosphorus MR spectroscopy in infants with
perinatal hypoxic-ischemic brain injury. They concluded
that when there were reduced values for phosphocreatine/
inorganic phosphate (PCr/Pi), indicating severely impaired
oxidative phosphorylation in the brains of these infants, the
prognosis for survival without serious impairments was very
poor, and that when adenosine triphosphate (ATP) and/or
total phosphorus was reduced, death was almost inevitable.19
They also put on a firm footing the notion that in newborn
infants with severe intrapartum asphyxia, there was a latent
period of a few hours after birth before energy failure became
detectable. This latency was thought to be due to a variety of
damaging sequelae initiated by the acute hypoxic-ischemic
episode and reperfusion of the brain. They proposed that
irreversible injury to brain cells after an episode of acute
hypoxia-ischemia may be prevented or ameliorated by the
prompt use of neuroprotective agents. The same group also
introduced the combined use of magnetic resonance spec-
troscopy (MRS) and near infrared spectroscopy (NIRS)
which gives cotside information about cerebral oxygenation
and hemodynamics.20
To appreciate the predictive value of the techniques men-
tioned in the preceding paragraphs, all infants at the Ham-
mersmith Hospital and also at University College Hospital
who survived the neonatal period were seen in a well orga-
nized follow-up clinic where specific neurodevelopmental
testing was performed. At the Hammersmith Hospital, they
were able to repeat the brain MRI scans of many children in
infancy and childhood and showed a good relationship for
site and pattern of injury between the neonatal and later
imaging and also with early outcome.21
Over the next decade, refinement of the techniques men-
tioned earlier improved our ability to predict neurodevelop-
mental outcome and our understanding of NE in the full-
term infant. At that time, clinical assessment of infants with
NE could be more difficult because of the introduction of
therapies, such as the use of muscle relaxants during treat-
ment of persistent pulmonary hypertension, and the greater
use of anticonvulsant drugs, particularly for treating subclin-
ical seizures recognized on continuous aEEG monitoring.
218
Cranial ultrasound improved with the use of higher reso-
lution transducers. Eken et al22 compared cranial ultrasound
findings with autopsy findings in 20 infants, additionally
using high resolution 10 MHz transducer to visualize the
cortex better, and found the technique reliable for lesions in
the thalamus (sensitivity 100%; specificity 83%), for cortical
lesions (77% and 100%), and for lesions in the white matter
(80% and 75%). Similar observations were made by Ruther-
ford et al23 in the same year, when they showed that the
incidence of abnormal findings in the BGT and periventricu-
lar white matter was much greater with MRI than with ultra-
sound. The infants were, however, particularly at risk of a
poor outcome when abnormalities were seen in the BGT on
MRI as well as on ultrasound. In contrast, a normal ultra-
sound or isolated findings of intraventricular hemorrhage,
subarachnoid hemorrhage, or transient flares were associated
with a normal outcome in infancy in ⬎90% of their infants.
Huge progress was made in the development of MR neu-
roimaging. MRI played an important role in visualizing the
abnormalities of the BGT and in understanding the timing
and evolution of injury. An important observation was made
by Rutherford et al24 in 1998, who recognized that an abnor-
mal signal intensity of the posterior limb of the internal cap-
sule (PLIC) was highly predictive of later abnormal neurode-
velopmental, and particularly motor outcome. The first study
was also performed in the Hammersmith Hospital,25 using
diffusion-weighted imaging (DWI) in newborn infants with
neonatal stroke The introduction of DWI helped to further
improve detection of BGT injury within days after onset of
the insult, and although time-dependent, calculation of the
apparent diffusion coefficient made the assessment of
changes more robust (Fig 2).26
aEEG became more widely used and the usefulness of early
assessment for prognosis in encephalopathic term infants us-
ing a multidisciplinary approach with a combination of cra-
Figure 2 Full-term infant with “acute near total asphyxia.” MRI (IR
sequence) (A) and diffusion-weighted imaging (DWI) (B). The IR
sequence shows mildly increased signal intensity in the lentiform
nuclei and thalami, and myelination in the posterior limb of the
internal capsule appears to be present though thin and not optimal.
These pathologic changes in the basal ganglia and thalami are better
seen with DWI, and increased signal intensity is also seen in the
hippocampi. The posterior limb of the internal capsule appears
abnormal on the DW image.
L.S. de Vries and F.M. Cowan
nial ultrasound Doppler, aEEG, visual EPs, and somatosen-
sory EPs was assessed by the Utrecht group in a group of 34
infants within 6 hours after birth.27 They noted that cranial
ultrasound and Doppler were often normal at this early stage
and the techniques were not informative unless already ab-
normal; when this was the case, outcome was almost uni-
formly poor and likely injury had occurred antenatally or had
been evolving for a long time before delivery. However, the
early aEEG and EPs were very predictive of outcome, both
good and poor. Because the aEEG was considerably less time
consuming to set up and less disturbing for the infant than
EPs and as it also allowed ongoing continuous monitoring,
this became the method of choice for early assessment in term
NE (Figs 3 and 4). The aEEG was subsequently shown to be
predictive of outcome as early as 3 hours after birth, making
it a suitable technique for selection of infants who could
benefit from neuroprotective intervention, such as hypother-
mia (Figs 3 and 4).28
A study from the Hammersmith group of 25 full-term
infants with NE, who had an EEG recorded within the first 72
hours after birth and a neonatal brain MRI scan after the end
of the first week, showed that both EEG and MRI were pre-
dictive of outcome. A normal MRI was always associated with
a normal EEG background activity and normal outcome, and
severe abnormalities on MRI were associated with marked
EEG abnormalities and an abnormal outcome. When the
MRI showed moderate abnormalities, the EEG, in all cases
but one, identified which patients would have a normal or
abnormal outcome.29
In 1993, the first studies using cerebral proton MRS in
hypoxic-ischemic injury were published from the group in
London and the group in Utrecht.30,31 The Dutch group ex-
amined infants at a mean age of 8 days and found a highly
significant reduction in N-acetyl aspartate and/or choline ra-
tio in infants with an adverse outcome compared with those
with a normal outcome; lactate was seen only in infants with
severe grades of hypoxic-ischemic encephalopathy (HIE).
The Hammersmith group subsequently studied case and
control infants within 18 hours of birth with 1H MRS and also
did later 31P MRS studies.32 In the asphyxiated infants, there
was a negative correlation between the ratio of lactate and/or
creatine in the first 18 hours after birth and PCr/Pi at 33-106
hours (P ⬍ 0.001). Again, poor PCr/Pi ratios predicted a poor
outcome. The lactate/creatine ratios were high in the 6 se-
verely affected subjects in the first 18 hours, suggesting that
after birth asphyxia, cerebral energy metabolism is abnormal
during the period when 31P MRS characteristically gives nor-
mal results. The Hammersmith group also showed that lac-
tate could be found much later than just the immediate peri-
natal period in infants with HIE, severe injury, and abnormal
neurodevelopmental outcome, but not in those with normal
neurodevelopmental outcome or in control subjects.33 These
data suggested both that pathologic postasphyxial processes
may not be confined to the period immediately after injury
and that treatments affecting these later processes may be of
benefit.
Follow-up was extended to early childhood. In a study of
68 infants (15 of whom had died and 19 of whom had cere-
Evolving understanding of HIE 219

Figure 3 The “integrated approach” in a full-term infant with neonatal encephalopathy. (A) single channel amplitude-
integrated electroencephalogram (aEEG), showing repetitive seizures on aEEG, confirmed on the raw electroenceph-
alogram below. There is some effect on the aEEG after phenobarbital administration; (B) coronal and (C) parasagittal
views of a cranial ultrasound examination showing slitlike ventricles and diffuse echogenicity in the thalami and the
white matter and low echogenicity in the cortex, giving an accentuated white matter-cortical signal difference. A
Doppler measurement taken from the middle cerebral artery (D) shows a low resistance index ⬍ 0.55, because of an
increase in diastolic flow.

bral palsy), it was found that some of the 34 who had been
considered normal at 2 years had minor neurologic dysfunc-
tion and/or perceptual-motor difficulties (15%), or only cog-
nitive impairment (2%), when assessed at early school age.34
The overall outcome of the whole group of infants strongly
reflected the pattern of lesions on neonatal brain imaging.
Although 83% of those with a normal outcome had normal
neonatal scans or minimal white matter lesions, 80% of those
with minor neurologic dysfunction and/or perceptual-motor
difficulties had mild or moderate basal ganglia or more
marked white matter lesions.
Figure 4 MRI (IR sequence) (A) of the same infant as in Figure 3,
performed on day 3, and apparent diffusion coefficient (ADC) map
(B) showing extensive abnormalities in the cortex and white matter,
more on the left side and some associated lesions in the basal gan-
glia.
Throughout this period and till the present time, the inci-
dence of NE thought due to hypoxia-ischemia has remained
relatively unchanged at about 1-2/1000 live full-term births,
and it still carries a high risk for subsequent neurodevelop-
mental disabilities.35 The rates are much higher in popula-
tions from less developed countries.36 The long-term out-
come relates to the severity of the neonatal condition, but is
better predicted from neonatal MRI than any other single
investigative modality.37,38
To define that the NE is secondary to perinatal asphyxia,
several markers are needed, such as abnormal fetal heart rate
tracings, poor umbilical cord gases, and low Apgar scores,
although individually, these markers have been shown to not
correlate very well with subsequent outcome.39,40 Indeed, a
very rigid system of defining intrapartum injury was pro-
posed by MacLennan,41 but acceptance of this has not met
with universal agreement.
NE is “a clinically defined syndrome of disturbed neuro-
logic function in the earliest days after birth in the term in-
fant, manifested by difficulty with initiating and maintaining
respiration, depression of tone and reflexes, subnormal level
of consciousness and often seizures”.2 The widely used 3 level
staging system of mild, moderate, and severe encephalopa-
thy, based on clinical symptoms and electoroencephalogra-
phy, was developed by Sarnat and Sarnat.2 The development
of encephalopathy in full-term infants within hours to days
after birth is now considered essential to be confident about
an underlying perinatal insult41 NE can develop for reasons
220
other than hypoxia-ischemia, for example, because of meta-
bolic disorders, and a combination of markers supporting the
presence of perinatal asphyxia as well as the development of
early NE is obligatory.
Many studies have investigated the underlying cause of
early encephalopathy from an epidemiologic perspective and
some in a defined population.42,43 These studies are often
retrospective or, if prospective, have not had sufficient data to
define the underlying cause of the encephalopathy. They
have, however, provided important data supporting the view
that for many infants it is possible to find antenatal events or
background maternal illness that suggests an onset of brain
injury or brain dysfunction before labor. They argue then that
the difficulties often documented in the course of labor and
delivery are secondary to fetal compromise predating labor,
and that evidence of poor oxygenation or fetal hypotension in
labor are not the prime cause of the encephalopathy. The
term “birth asphyxia” is now no longer used, and even “hy-
poxic-ischemic encephalopathy” is a diagnosis used with cir-
cumspection and only when other etiologies of encephalop-
athy have been excluded and there is positive evidence to
support this. This process can be difficult and thus the term
“neonatal encephalopathy” has come into vogue; this is cor-
rect, but it is all encompassing and not necessarily helpful.
Identifying antenatal factors that may increase the risk of
susceptibility to or intolerance of stress in labor does not
prove that the brain damage responsible for the adverse long-
term outcome did not occur in labor; this is supported by the
widespread observation that babies born by prelabor cesar-
ean section for nonfetal reasons rarely develop an encepha-
lopathy unless they have a specific metabolic or developmen-
tal problem.
The Hammersmith and Utrecht group combined their
neonatal MRI data obtained within 2 weeks after birth from
360 full-term infants with NE.44 They found that ⬎90% of
these infants had evidence only of perinatally acquired le-
sions on their MRI, with a very low rate of established ante-
natal brain injury or other confounding diagnoses. Addition-
ally, they did not find high rates of antenatal problems in
these cohorts. These data were not obtained from a popula-
tion base, but they provide evidence that antenatally estab-
lished damage in infants with an acute encephalopathy is not
common. The data do not, of course, exclude damage occur-
ring or starting just before labor or early in its course. Since
then, there has been some return to the view that intrapartum
difficulties are relevant for a significant proportion (35%) of
term-born infants with both NE, and of those who develop
cerebral palsy.45
Although NE is generally considered a disorder affecting
term or near-term infants, it may also affect the preterm in-
fant. Clinically, it is more difficult to define the encephalop-
athy because the symptoms are either not recognized or may
occur in preterms for other reasons, and the use of the Sarnat
staging has not been tested in this population. However, the
injury which is often not recognized early can often be severe
and outcome is poor.46,47
L.S. de Vries and F.M. Cowan
Where Are We Now?
At the beginning of the 21st century, we are using more or
less the same battery of tests for assessing infants with NE that
were introduced in the preceding 20 years, with modifica-
tions and optimizations.
Clinical Assessment
Clinical assessment has not really changed, but the introduc-
tion of hypothermia treatment for HIE has led to more formal
documentation of early neurologic states. The Thompson
score48 is now increasingly used, as this assessment has been
shown to differentiate between good and poor outcomes
even within the first hours after delivery in comparison with
the Sarnat classification that becomes reliable only 24 hours
after birth2 However, as with all clinical examinations, the
use of different treatment regimes and co-occurring illness
makes early prediction of outcome on clinical grounds alone
unreliable.49
Cranial Ultrasound
Cranial ultrasound has unfairly not been regarded as partic-
ularly useful, but it does play an important role and is very
useful when performed with good equipment and experi-
ence.50,51 A cranial ultrasound scan should be done on ad-
mission for any infant with NE, to document that there is no
major developmental abnormality that may account for the
symptoms; that there are no signs that might suggest a con-
genital infection or a metabolic disorder, for example, calci-
fication, germinolytic cysts, lenticulostriate vasculopathy and
unusual cortical folding in Zellweger syndrome, or a hypo-
plastic corpus callosum and mild uniform white matter echo-
genicity in nonketotic hyperglycinemia; and that there is no
evidence of long-standing injury.52,53 Furthermore, the pres-
ence of echogenicity in the white matter or the basal ganglia
on the admission examination, without atrophy, is highly
suggestive of a recent but probably prelabor onset of an in-
sult, which has led to NE and needs to be taken into account
when looking at underlying risk factors and the effects of
intervention, such as hypothermia. Such information is not
only very important clinically but has major medicolegal im-
plications. Leijser et al54 were able to show that predictive
value of an abnormal signal intensity of the PLIC on MRI
could also be recognized on cranial ultrasound, seen as a line
of reduced echogenicity in between areas of increased echo-
genicity in the BGT. There was a strong correlation between
seeing the PLIC on ultrasound and both loss of the normal
PLIC signal on MRI and motor outcome. Although there is no
question that MRI is superior to ultrasound for prognosis in
NE, ultrasound can give important early information and can
be used to document the evolution of lesions, and is an im-
portant tool, particularly in many places where MRI is not
available. A normal ultrasound scan with no evidence of at-
rophy in association with good head growth gives very useful
Evolving understanding of HIE 221

prognostic information at early follow-up in situations where although less common than the patterns outlined earlier in
MRI is not available. the text. Li et al59 pointed out that infants with this type of
injury are significantly less mature and tend to have a milder
encephalopathy and fewer clinical seizures relative to new-
Magnetic Response Imaging borns with the 2 more common patterns of injury.
With the wider use of MRI, the recognition of different pat- Perinatal arterial ischemic stroke and perinatal hemor-
terns of injury has become established; 2 main patterns are rhagic stroke can occur, but these lesions are usually not
clearly distinguished: related to perinatal asphyxia and are therefore outside the
scope of this review.60,61
1. A basal-ganglia-thalamus pattern predominantly affect-
Although MRI is considered superior in recognition of the
ing bilaterally the central gray nuclei and perirolandic
patterns mentioned in the preceding paragraphs, Chau et al
cortex. Associated involvement of the hippocampus
recently showed that the agreement for the pattern of injury
and brain stem is not uncommon. This pattern of injury
was also good for CT and diffusion-weighted MRI (67%
is most often seen after an acute sentinel event and is
agreement). The extent of cortical injury and focal-multifocal
also referred to as a pattern following “acute near total
lesions, such as strokes and white matter injury, were, how-
asphyxia.”55,56 This pattern is typical of the term infant,
ever, less apparent on CT than on diffusion-weighted MRI.62
but in preterm infants it tends to affect the lower basal
ganglia and brainstem and spare the cortex.46,47
2. The watershed predominant pattern of injury affecting Later Imaging
mainly the white matter and, in more severely affected
Long-term effects seen on brain imaging after NE of hypoxic-
infants, also the overlying cortex in the vascular water-
ischemic origin are now being studied, and a reduction in
shed zones (anterior-middle cerebral artery and pos-
especially the posterior part of the corpus callosum was
terior-middle cerebral artery).57 The lesions can be
found to be associated with a poor performance on the Move-
uni- or bilateral and predominantly posterior and/or
ment-ABC, relating structure to motor function in children
anterior. Although loss of the cortical ribbon, and
without cerebral palsy.63
therefore the gray-white matter differentiation, can be
Using new MRI techniques, such as diffusion tensor imag-
seen on conventional MRI, DWI highlights the abnor-
ing and fractional anisotropy maps, Nagy et al64 showed that
malities and is especially helpful in making an early
even in adolescents who had not developed cerebral palsy
diagnosis (Fig 5).57 A repeat MRI may show cystic evo-
after HIE, fractional anisotropy values were lower in white
lution, but more often atrophy and gliotic changes will
matter compared with controls, in regions including the cor-
be recognized.23 This pattern of injury is typically
pus callosum and the internal capsule.
thought to be seen following “prolonged partial as-
phyxia.” It is also more common after hypotension,
infection, and hypoglycemia, all of which may be asso- Electrophysiology
ciated complications of more prolonged partial as-
aEEG was used as one of the selection criteria for the CoolCap
phyxia (Fig 5).57,58
and TOBY trials.65,66 In the former it was shown that infants
Additionally, there are infants with lesions restricted to the with severely abnormal background activity were less likely
periventricular white matter not dissimilar from the so-called to benefit from hypothermia.65 In an MRI study comparing
punctate white matter lesions described in preterm infants; lesions in infants who were cooled and not cooled, the bur-
these can be distinguished as a separate pattern of injury, den of lesions was less in the cooled infants and less in those

Figure 5 Full-term infant with “prolonged partial asphyxia.” (A) Transverse neonatal MR (IR sequence) image, and (B)
DWI performed on day 5, showing cortical highlighting and low signal intensity in the white matter on the IR. The
increased signal intensity on DWI is very striking around the Sylvian fissures, in the corpus callosum, and in the
posterior watershed zones, with sparing of the central gray matter. (C) Gliotic changes were seen in a same distribution
on the fluid attenuated inversion recovery (FLAIR) sequence at 2 years of age.
222
whose aEEG was classified as moderate compared with se-
vere. However, in this study, the infants were not random-
ized, and this observation, although likely to be real, should
be tested in a larger randomized study.67
The first randomized controlled trial for the treatment of
subclinical seizures was initiated by the Utrecht group. Al-
though the number of infants enrolled was small, it was of
interest to see that the seizure burden was reduced in those
treated for clinical as well as subclinical seizures and the MRI
score was higher, indicating more lesions in those who re-
ceived therapy only for clinical seizures.68 Further support of
the potentially harmful effect of neonatal seizures on subse-
quent outcome was given by Glass et al69 They studied 77
newborn infants at risk of neonatal seizures and assessed with
neonatal MRI. Those with neonatal seizures were noted to
have worse motor and cognitive outcomes compared with
those without seizures, after controlling for severity of injury
on MRI. The magnitude of effect varied with seizure severity.
aEEG is now available as a digital device with simultaneous
access to the raw EEG, and 2-channel recordings rather than
a single channel are now most widely used, allowing us to
diagnose unilateral lesions at a time when infants present
with focal seizures and MRI is still awaited. With 2-channel
aEEG and access to the EEG, about 80% of seizures can now
be recognized.70 Seizure-detection algorithms are being de-
veloped and have already shown their potential value.71 Con-
tinuous aEEG recordings will be increasingly used to see the
effect of (new) antiepileptic medication, to be studied in mul-
ticenter randomized controls.
Combining aEEG and NIRS, Toet et al72 showed that the
regional oxygen saturation (rSo2) increased and the frac-
tional cerebral tissue oxygen extraction decreased after 24
hours in infants with an adverse outcome. The aEEG data
gave the closest relationship with outcome; the rSo2 also
showed a significant correlation but only at 24 hours after
birth. The combination of an increased rSO2 and de-
creased fractional cerebral tissue oxygen extraction re-
flects less use of oxygen by brain tissue because of neuro-
nal cell death, with a consequent decrease in uptake of
oxygen by the brain.
Magnetic
Resonance Spectroscopy
Although still not widely used, MRS is especially helpful
when an MRI is performed on day 1, when changes on con-
ventional MRI are often restricted to cerebral edema and at a
time when changes in the PLIC are not yet visible and DWI
changes may still become more extensive.73,74 Chemical shift
imaging is now also available, giving an image of N-acetyl
aspartate and lactate distribution rather than spectra taken
in a specific region of interest. MRS is also very useful in any
infant in whom another or additional cause for encephalop-
athy is suspected, for example, nonketotic hyperglycinemia
and mitochondrial disorders.
L.S. de Vries and F.M. Cowan
Follow-Up
Most studies reported so far have focused on early neurode-
velopmental outcome at 18-24 months, looking mainly at
development of cerebral palsy or severe cognitive deficits.75
Infants with mild NE have been reported to have a normal
outcome, whereas those with severe NE will either die or
invariably develop cerebral palsy and cognitive deficits.34,37,76
Pin et al38 reviewed 13 empirical studies meeting strict inclu-
sion criteria, and found no adverse outcome under 3 years in
infants with mild NE, but outcome was poor in 32% of those
with moderate NE and almost all of those with severe NE.
Very similar data were found in an earlier review by Di-
lenge.77 The infants with moderate NE have a variable out-
come, and other techniques, such as neuroimaging tech-
niques, in particular MRI, and neurophysiological tests,
especially aEEG and EPs, are required to more accurately
predict neurodevelopmental outcome.27,78
Only a few studies provide detailed assessment of longer
term outcome.34,76,79 The American College of Obstetricians
and Gynecologists task force on NE and cerebral palsy made
a statement that an acute intrapartum event (most often as-
sociated with a sentinel event) could only result in cerebral
palsy of the tetraplegic or dyskinetic type and could not result
in isolated cognitive deficits.41 This view has been held for a
long time.
A recent review by Gonzalez and Miller,80 however, pro-
vided data showing that survivors of NE after perinatal as-
phyxia are at increased risk of cognitive deficits, even in the
absence of motor deficits. This finding agrees with data pub-
lished in 1989 by Robertson et al,76 looking at long-term
outcome at 5.5 and 8 years after NE. They found that non-
disabled survivors of moderate NE were similar to controls
with respect to receptive vocabulary and perceptual motor
skills, but showed marked delays in reading, spelling, and
arithmetic. These children were more likely to be at least 1
grade behind controls or behind those with mild NE.
A recent study by Marlow et al79 analyzed 65 children with
NE at 7 years of age, who were testable using standard tests of
cognition and language. They classified infants as having
moderate NE when they presented in the first week after birth
with either seizures alone or any 2 of the following: abnormal
consciousness, difficulty maintaining respiration (of pre-
sumed central origin), difficulty feeding (of presumed central
origin), and abnormal tone and reflexes, with all lasting ⬎24
hours. The children with severe NE had to fulfill one or more
of the following criteria: ventilation for more than 24 hours,
2 or more anticonvulsant treatments required, and are coma-
tose or stuporous. Of note, requiring ventilation and 2 or
more anticonvulsant drugs would be considered moderate
NE by most clinicians, so some of the children classified as
having severe NE may represent more severely affected mod-
erate NE children. No neonatal imaging or electrophysiolog-
ical data were available for these children, although no chil-
dren with a diagnosis other than encephalopathy as a result of
presumed hypoxia-ischemia were included. They reported
that those with moderate NE were not different from controls
with respect to general cognitive ability, but were lower in
Evolving understanding of HIE
language and sensorimotor domains, as well as narrative
memory and sentence repetition. The children were more
likely to require extra educational assessment, teaching pro-
vision and support, even though they did not have any overt
neuromotor impairment. Among the more severely affected
children, referred to as severe encephalopathy, memory for
names, orientation, and reported everyday memory function
were also significantly poorer than for either comparison
children or the moderate encephalopathy group.
Specific memory impairment has been the topic of recent
studies, initially noting a specific and severe impairment of
episodic memory (context-rich memory for events) with rel-
ative preservation of semantic memory (context-free memory
for facts).81 Since then, others have found problems in verbal
learning and/or recall and in visual recall in school-aged chil-
dren and adolescents with moderate NE. These findings
stress the importance of detailed examination of the develop-
mental effect of NE on memory function.82,83
Long-Term
Outcome into Adolescence
Data on long-term outcome are scarce and often lack sophis-
ticated neonatal neuroimaging data. In a recent study by
Lindström et al,84 of children aged 15-19 years with moder-
ate NE, most had cognitive deficits (81%). The children were
considered eligible for the study based on an Apgar score ⬍7
at 5 minutes and meeting clinical criteria for moderate NE. Of
56 eligible children, 13 did not agree to participate. Of the 43
children who did participate, 13 (30%) had cerebral palsy,
22 (51%) had cognitive dysfunctions without cerebral palsy,
and only 8 (19%) had no obvious impairments. A first study,
using diffusion tensor imaging, showed long-term white mat-
ter disturbances that persist into adolescents with moderate
HIE in a small group of 8 teenagers.64
More recently, studies have shown a relationship between
the patterns of injury as recognized with neonatal MRI and
later neurodevelopmental outcome. The children with the
BGT pattern of injury are often so severely disabled that they
will not be included in long-term follow-up studies.85 Ability
to sit by 2 years of age and walk by 5 years of age occurred in
only a minority of a group of children who showed involve-
ment restricted to the lentiform nuclei and ventrolateral thal-
amus, whereas those with more extensive injury, including
injury to the perirolandic cortex and hippocampus, were not
able to reach these goals.86 Himmelmann et al85 studied 48
children at a mean age of 9 years (range 4-13 years) with
dyskinetic cerebral palsy mostly because of BGT injury, and
found that most had a severe motor disability (Gross Motor
Function Classification System levels of IV and V). The rates
of learning disability (35 of the 48) and epilepsy (30 of the
48) in this group were high and increased with the severity of
the motor disability.
Children with a watershed-predominant pattern of injury
seldom have severe motor impairment and are not uncom-
monly considered to have an early normal outcome when
seen at 12-18 months, and are then discharged from further
223
follow-up. However, suboptimal head growth,87 behavioral
problems, squint, and delays in language acquisition are
common. Several studies have now shown that they “grow
into their deficits” and it is this group in particular that needs
follow-up well into early childhood. Miller et al88 were first
able to recognize cognitive deficits associated with the water-
shed pattern of injury at 30 months, while the problems were
largely overlooked when seen at 12 months. More recently,
the same group also showed a correlation with verbal IQ at 4
years of age.89
Conclusions
Over the last 3 decades, enormous progress has been made in
the diagnosis and early prediction of outcome in full-term
infants with NE. Some of the techniques that have been de-
veloped can be performed continuously and at the bedside
(cranial ultrasound and Doppler, aEEG, EPs, and NIRS),
whereas others need transportation of the infant (MRI/MRS).
Predictive values of some of these techniques may change
with the introduction of an intervention, such as hypother-
mia, which may have an effect on the aEEG or on MRI.
It has become increasingly clear that childhood survivors
of NE, including those without cerebral palsy, are at in-
creased risk of cognitive, behavioral, and memory problems.
Now, longitudinal monitoring of educational and behavioral
development is recommended in children with all degrees of
NE, as we have become aware that the children without ob-
vious motor deficits may still be at risk of having problems at
school. Long-term follow-up is also essential to appreciate
fully the effect of new neuroprotective and, hopefully, repar-
ative strategies that are being and will be introduced over the
next few years. Long-term studies of infants treated with
hypothermia are awaited.
It is hoped that in the future, there will be more popula-
tion-based case-control studies of NE detailing information
on antenatal and perinatal events together with early electro-
physiology and brain imaging, to define the pattern of lesions
and timing of lesion onset. It is essential that such studies
have appropriately chosen and studied controls to under-
stand the role of antenatal prelabor factors in the etiology of
NE and also, and likely more importantly, the significance of
events and management of labor. Prevention of this devastat-
ing problem that seems mostly to affect fetuses thought to be
developing normally throughout pregnancy up to term age
should be the ultimate goal.
Acknowledgments
The authors appreciate all the researchers whose work has
been discussed in this review—in particular they thank Drs
Floris Groenendaal and Mona Toet in Utrecht and Prof. Mary
Rutherford in London for their particular contributions.
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