Early Human Development 120 (2018) 75–79

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Early Human Development

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MRI as a biomarker for mild neonatal encephalopathy T

A R T I C LE I N FO A B S T R A C T

Keywords: Historically, there has been limited neuro-imaging data acquired on infants with mild neonatal encephalopathy
Magnetic resonance imaging (NE). This likely reflects the traditional assumption that these infants had a universally good prognosis. As new
Perinatal asphyxia evidence has emerged challenging this assumption, there has been a renewed interest in the neuro-imaging
Mild neonatal encephalopathy findings of these infants. To date, magnetic resonance imaging (MRI) studies in infants with mild NE have
Hypoxic ischemic encephalopathy
demonstrated abnormalities in 20–40% of cases suggestive that the injury occurs during the peripartum period
Biomarker
with a predominant watershed pattern of injury. The severity of the injury on MRI in infants with mild NE varies,
but includes patterns of injury that have been associated with long-term neuro-developmental impairment.

1. Introduction 2. MRI in neonatal encephalopathy

Perinatal asphyxia, around the time of delivery, can result in a hy-
poxic-ischemic (HI) insult to the brain. If severe enough, this HI insult
causes neural injury and the clinical syndrome termed neonatal en-
cephalopathy (NE). NE remains a major cause of mortality and mor-
bidity among newborns, occurring in approximately two to five infants
per 1000 live births [1]. The potential long-term morbidities following
NE include cerebral palsy, cognitive impairments, epilepsy, blindness
and hearing impairments [2]. While long-term neurodevelopmental
follow up remains the gold-standard to identify these outcomes, mag-
netic resonance imaging (MRI) has been proven to be a robust surrogate
predictor. It has the advantage of being able to delineate the initial
brain injury sustained, and highly correlates with long-term outcome
even when performed in the first days of life [3,4].
The frequency of morbidities among infants with NE is associated
with the severity of the initial encephalopathy [5]. Infants with mod-
erate to severe NE are reported to have at least a 50% to 80% incidence
of significant neuro-developmental disability, respectively [6], while
those with mild NE were classically considered to have a good prog-
nosis [2]. For this reason there has been very limited published MRI
data on those mild NE. However, there is increasing evidence demon-
strating that neuro-developmental impairments occur in a significant
number of those with mild NE [7–10]. Given the lack of published
neuro-imaging data on these infants, and the emerging evidence for
long-term impairment occurring, several research groups have now
begun to study the imaging findings in these infants in detail.
This paper will review the use of MRI in infants with NE, and the
evidence for brain injury occurring in those with mild NE. Specifically,
the data will be presented from recent cohorts detailing the frequency,
severity and pattern of brain injury that occurs among those infants
with mild NE.
MRI studies have documented the distribution and frequency of
brain injury associated with NE. The commonest injury patterns involve
either injury to the watershed (WS) region, or to the deep grey nuclei
consisting of the Basal Ganglia and Thalamus (BGT). The WS region
refers to the intravascular border zone. Injury in this region involves the
periventricular white mater, and may extend out to involve the cortex
with increasing severity [3]. WS injury is classically associated with
sub-acute asphyxia, hypotension and impaired autoregulation, [3,11]
and occurs in 40–60% of HI cases [1]. Contrary to this, injury to the
BGT is associated with acute severe asphyxia, and occurs in 40–80% of
cases [1,3,11]. A less common, but potentially catastrophic pattern of
injury following severe asphyxia, is that associated with both BGT and
brainstem injury, occurring in 15 to 20% of cases [1]. Other specific
structures that have been repeatedly demonstrated to be associated
with HI injury and outcome include the hypothalamus, and internal
capsule [12,13]. Several MRI grading system of brain injury following
perinatal asphyxia have been developed from this data [3,14,15]. Al-
though the grading systems differ, they each have been extensively
validated, and demonstrated to be highly predictive of long-term out-
come among both normothermic and hypothermic infants with NE
[14–16].
2.1. Timing of MRI in neonatal encephalopathy
Cerebral injury following a hypoxic-ischemic insult in a term born
infants is most evident on conventional T1 and T2 echo sequences be-
tween the first and second weeks of life [17]. Limitations on the ac-
quisition of MRI during the first few days after delivery often relates to
the fact that infants with NE may be typically unstable from a cardi-
orespiratory point of view making transport out of the NICU challen-
ging. For these and other reasons of optimal visibility of the full extent
of the cerebral injury, standard clinical practice evolved to perform MRI

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scans between days 10 to 14 on these infants. The introduction of dif-
fusion weighted Imaging (DWI) in the 2000s altered practice as MRI
abnormalities became visible earlier.
DWI can demonstrate injury from the first day of life. The diffusion
restriction is maximal in normothermic infants on days two to three and
will then slowly normalize, often before the injury is evident on con-
ventional sequences. This ‘pseudo-normalization’ occurs at about days 6
to 8 of life in normothermic infants, but is delayed until days 11 to 12 in
infants that receive TH [18,19]. With the ability to detect injury early,
many clinicians have now chosen to perform both an early scan, after
the completion of TH, and a later scan in the second week of life. The
advantages of performing two scans includes; being able to provide
families and clinicians information on the presence of brain injury
sooner; ensuring that the true extent of the injury is documented on the
later conventional sequences; and assistance in timing of the injury
given the known evolution of the injury patterns from DWI to con-
ventional sequences.
Recent publications have demonstrated that DWI imaging is highly
correlated with outcome. However, there have been limited serial MRI
scans in infants with NE to ensure that the injury does not evolve fur-
ther between the early and late scans. Therefore, as most of the pub-
lished outcome data has relied on the later conventional T1 and T2
sequences [3,4,13], the later scan continues to be performed to confirm
the extent of the injury. This has significant implications in particular
for infants with mild NE who are typically discharged earlier than those
with more severe encephalopathy. Within our own cohort, while the
median duration of admission for infants with both moderate and se-
vere NE was 11 days, for infants with mild NE it was only 8 days (IQR 6
to 12). Therefore most infants with mild NE were being discharged
prior to a late MRI being performed. The need to return following
discharge to ensure accuracy of extent of injury has obvious concerns.
Fortunately several recent studies have now demonstrated the va-
lidity of the earlier scan to determine the ultimate extent of the injury
[20,21]. Chakkarapani et al. compared early (days 3 to 6) and late
(days 10 to 14) MRI scans performed on 43 cooled infants. They re-
ported excellent agreement for both the predominant pattern of injury
(κ = 0.89), and injury severity (BGT predominant severity κ = 0.67,
WS predominant severity κ = 0.87), between the early and late scans.
Similarly the study of Skranes et al. compared the imaging findings
between MRI scans performed early (days 3 to 7) and late (days 9 to 27)
in a cohort of 41 cooled infants. Again the authors found excellent
agreement for the severity of brain injury present (κ = 0.85), between
the early and late scans. Therefore, while not dismissing the additional
benefits of a second scan, these studies can reassure the clinician that
the prognosis and severity of injury is more likely than not to remain
the same. In our experience, consistent with that reported above,
around 15% of MRs will demonstrate a change in characteristic from
the early (2–5 days) to later (7–21 days).
3. MRI in mild neonatal encephalopathy
As stated above, infants with mild HIE were previously considered
to have a favourable outcome, and were not included in the therapeutic
hypothermia trials. For these reasons, since the introduction of cooling
there has been limited research focusing on the MRI injury that occurs
with mild encephalopathy. Despite this, there has been published data
demonstrating MRI injury among infants with mild NE for several
decades [4].
Mercuri et al. recruited a cohort of 52 infants with HIE between
1991 and '98. All infants underwent an MRI consisting of conventional
T1, T2 and inversion sequences within the first month of life. Within
their cohort, 37 infants had moderate and 15 had mild encephalopathy
[22]. While the frequency of an abnormal MRI was greater among those
with moderate NE, occurring among 94% [35], there remained a sig-
nificant minority of infants with mild NE, 34% [5], that demonstrated
MRI injury. The MRI abnormalities among those with mild NE consisted
76
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Early Human Development 120 (2018) 75–79
of both white matter injury (WMI), and basal ganglia injury. Similarly
the early work on MR spectroscopy (MRS) demonstrated lactate peaks
occurring frequently among those with mild NE (84%) when imaged in
the first day of life, and that the lactate to creatinine ratios were fre-
quently higher in those with mild compared to moderate NE [23].
A further study was that of van Kooij et al. which performed serial
MRI scans during both the neonatal period and late childhood on a
cohort of infants with NE. In their study, van Kooij et al. found that half
of those with mild NE had significant MR injury during the neonatal
period. Perhaps more importantly they found that approximately half
continued to have an abnormal MRI (18/33) in late childhood [24].
Thus proving that the MR abnormalities among those with mild NE are
not transient, but represent true injury.
While many studies now define the grade of encephalopathy based
on the early assessment when determining the need to provide TH, one
of the true strengths of these older cohort studies is that they defined
the grade of encephalopathy as the most severe grade demonstrated
during the first week of life, in keeping with the work of Robertson and
Finer [2,22,24]. We can therefore be confident in the grading provided,
and can disregard the argument that those with mild NE and MRI injury
represent infants whose encephalopathy evolved and worsened over
time. Rather we can state that MRI injury truly does occur among those
with mild encephalopathy.
3.1. Frequency of abnormal MRI in mild neonatal encephalopathy
Given the limited published data that has focused on mild NE, it has
been difficult to detail the true incidence of both any MRI abnormality,
and more specifically MR injury consistent with hypoxia-ischemia (HI),
among this population. The Children's Hospital Neonatal Database have
recently reported on one of the largest datasets of infants with mild NE
[25]. In their network they found that of 132 infants with mild NE, 59%
(79/132) had an abnormal MRI. However, the exact nature of the injury
is not well defined in the dataset, and therefore difficult to determine if
the injuries were consistent with hypoxia-ischemia or represented a
range of pathologies. Data published by our own group further illus-
trates this point [26]. Of 48 infants with mild NE, we found that 54%
(26/48) of infants had an abnormal MRI. HI injury represented the
majority of MRI abnormalities detected, being present in 38% of the
entire population, and 70% of those with an abnormal MRI. Other
abnormalities detected on MRI included interventricular haemorrhage,
isolated cerebellar lesions and areas of gliosis. While these are im-
portant findings, and further support the need to image these infants,
they are important to differentiate from typical HI injury, especially as
we consider potential neuroprotective strategies in this population.
3.2. Hypoxic-ischemic brain injury in mild neonatal encephalopathy
There is some variation in the reported incidence of MRI defined
hypoxic-ischemic cerebral injury in infants with mild NE. As noted
above, our cohort reported that hypoxic-ischemic cerebral injury oc-
curred in 38% of those with mild NE. Two alternate cohort studies have
recently reported significantly higher rates of 60–100% hypoxic-is-
chemic cerebral injury on MRI among infants with mild NE. However
the sample sizes were small [27], and one was conducted in a low re-
source setting with potential confounding variables [9]. One of the few
other cohort studies with a similar sample size to our own, supported
our findings reporting very similar results [28]. The authors recruited
all infants referred to their centre for consideration of TH. Within this
cohort, 63 infants with mild NE had an MRI performed, and 38% (24/
63) were found to have MRI injury consistent with HI. It must be noted
that a common limitation of these recent datasets is the potentially
confounding use of TH.
There is an increasing ‘off-label’ use of therapeutic hypothermia
among infants with mild NE. Current reports suggests that at least 50%
of infants with mild NE are now offered therapeutic hypothermia [29].
 Early Human Development 120 (2018) 75–79

As a result most recent studies have detailed the incidence of MRI injury Table 1
in mild NE among populations within which at least a sizeable minority Details of studies providing MRI outcome in infants with mild NE.
have received therapeutic hypothermia [25,26,28]. In infants with Author Year MRI Mild NE % cooled %
moderate and severe NE, TH is known to reduce the frequency of MRI classification cases (n) abnormal
abnormalities [14,16,30]. Although animal data would suggest that TH MRI
should improve WMI among those with mild NE [31], there is no
Mercuri [22] 2000 Rutherford 15 0 34
human data assessing the impact of TH on the MRI findings in mild NE. Van Kooij [24]a 2010 Swarteb 6 (newborn 0 66
As such it remains unclear if the use of TH in these cohorts impacted on MRIs)
the frequency of HI injury they described. 33 0 55
The prospective multicentre PRIME study was designed and con- (childhood
MRIs)
ducted to over-come some of these limitations, limiting their inclusion
DuPont [27] 2013 Barkovich 9 0 66
criteria to only recruit infants with mild NE that did not receive TH Lally [9] 2014 Rutherford 29 0 100
[32]. These infants underwent MRI imaging within the first month of Massaro [25] 2015 c
132 c
59
life and have been enrolled in long-term follow up. The PRIME study Gagne-Loranger 2016 Barkovich 63 21 38
[28]
confirmed the presence of significant MR injury following mild NE. In c
Lally [37] 2017 10 100 50
their cohort of 54 infants, 17% (9/54) demonstrated MR injury con- Prempunpong 2017 NICHD 54 0 17
sistent with hypoxic-ischemic insult. Further insight is provided by the [32]
study of Gagne-Loranger et al., which although included both those that Walsh [26] 2017 Barkovich 48 100 38
did and did not receive TH, the results presented allowed analysis of a
both groups independently [28]. Their cohort reported on a similar 33 children with mild NE in cohort- all had childhood MRI, only 6 had
neonatal MRI.
number of infants with mild NE that did not receive TH (n = 50) to the b
Modification and expansion of Barkovich system [38].
PRIME study, however they reported a higher frequency of HI MRI c
Not specified.
injury, 40% (20/50). The variation in the frequency of MRI injury re-
ported between these studies is potentially related to the relatively
recognition therefore that injury in mild NE typically occurs during the
small sample sizes, such that some variation would be expected, and to
intra-partum period is important as we look to the future, and consider
the differences in MRI grading systems utilized. Of note in the study by
how best to manage these infants.
Gagne-Loranger et al., the infants that did receive TH, all had clinically
mild NE but were treated due to an abnormal aEEG pattern on pre-
sentation. Despite the fact that they appeared to have potentially worse 3.4. Pattern of hypoxic ischemic injury in mild neonatal encephalopathy
encephalopathy at baseline, they actually had a lower incidence of HI
MRI injury than those that were not treated with TH in that cohort, 31% In a study of 173 infants with NE, Miller et al. defined the MRI
(4/13) versus 40% (20/50), respectively. However while these results injury pattern on conventional sequences as; Normal, WS predominant
are provocative, it is recognized that the sample sizes are too small to or BGT predominant. In their cohort they found that infants with milder
infer any association between TH and decreased frequency of injury on encephalopathy were likely to have either normal or WS predominant
MRI. MRI findings, while those with more severe encephalopathy had BGT
From the available data we can therefore state that MRI abnorm- predominant patterns [33]. In a subsequent cohort of 48 infants with
alities and HI injury are frequent among infants with mild NE (Table 1). NE, Miller's group additionally demonstrated that WMI, was more fre-
We would expect that 50 to 60% of those with mild NE would have quently associated with milder rather than severe encephalopathy [34].
some abnormality on their MRI brain, while approximately 20 to 40% In these cohorts they defined the encephalopathy using a validated
of these infants would demonstrate MRI abnormalities consistent with score, but one that does not directly translate to the Sarnat staging
HI injury. system [5]. Therefore while this work demonstrated that WS and WMI
injury are typical of less severe encephalopathy, it was not possible to
3.3. Timing of hypoxic ischemic brain injury in mild neonatal state if the injury was indicative of mild versus moderate NE. We would
encephalopathy however expect that the injury found in those with mild NE should have
a predominant WS pattern, with a greater burden of injury within the
The timing of brain injury is often difficult to accurately determine. white matter.
It is known that the majority of cases of HI injury occur intra-partum, In our own cohort of full term infants with NE, as expected, we
while a minority occur in the ante-partum (5–20%) and post-partum (5 demonstrated that those with mild NE had greater injury in the WS
to 10%) periods [1]. Additionally the neurological syndrome of NE is regions. Specifically among all infants with mild NE, 36% had injury
not static but is rather a dynamic syndrome. It increases to a maximum within the WS regions, while only 4% demonstrated an injury in the
grade, and then improves back through lower grades until resolution of BGT. This contrasted significantly to those with severe NE, among
the encephalopathy. This further complicates our ability to determine whom 50% had injury to the WS regions, and 34% to the BGT. These
the timing of injury based upon clinical assessment alone. As discussed results have been replicated by several recent cohort studies, which
previously, while MR imaging cannot exactly pin-point the time at have consistently shown that mild NE is associated with injury to WS
which HI injury occurred, DWI sequences and serial scans can provide regions, impacting the cortex and white matter, with only a small
insight into the approximate timing of injury, and its evolution. minority demonstrating injury in the deep grey nuclei [9,24,27,28,32].
The majority of infants with mild NE in our cohort had two MRIs
performed [26]. An early scan in the first week of life (median day 4, 3.5. Severity of hypoxic-ischemic brain injury in mild neonatal
inter-quartile range [IQR], days 4–5), and a late scan in the second encephalopathy
(median day 12, IQR days 9–14). The early scans demonstrated re-
stricted diffusion associated with the HI injury in 95% of cases. By the Neuro-developmental outcome following mild NE is known to be
later scan, the HI injury was confined to the conventional sequences. variable. While older studies indicated that these infants did well [2,5],
This data indicates that in the vast majority of infants with mild NE, the more recent studies have consistently demonstrated deficits on stan-
HI injury occurred during the intra-partum period. Current neuro-pro- dardized testing [7,8,10]. The use of MRI has allowed us to demonstrate
tective strategies necessitate that treatment me provided rapidly after the range of injury severity sustained, and that the injuries pre-
the insult has occurred to prevent secondary energy failure. The dominantly occur within the WS region, impacting the cortex and white

77

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matter. These findings may help to explain some of the variation in
outcome that has been reported between studies. Injury to the deep
grey nuclei has consistently been reported to have a strong association
with both motor and cognitive outcome [35]. Injury to the white mater
and cortex is far more variable [36]. In particular lower grades of WMI
frequently do well on gross neuro-developmental assessment, however
it remains possible that more subtle deficits may remain among these
infants.
Additionally the injuries described within each of these cohorts
represent a range of severity, with an associated range in prognosis. The
higher grades of MRI injury are known to highly correlate with poor
neuro-developmental outcome, while the milder injuries have a more
variable outcome. However even among these less severe injuries there
remains a significant risk of impairment. In the PRIME study the ma-
jority of MR injuries were isolated cerebral lesions (77%), typically
sparing the deep grey nuclei, classified as pattern 1a and 1b on the
NICHD-NRN MRI scoring system. While these represent milder patterns
of injury on the scoring system, they are still associated with moderate
to severe neurodevelopmental impairment in 17 to 25% of cases. Not all
lesions in the PRIME study spared the deep grey nuclei however, with
cases of more extensive injury involving both the BGT and cerebrum
being reported also. Although less common, these more severe injuries
are associated with a much higher rate of impairment, with moderate to
severe neuro-developmental impairment occurring in up to 70% of
cases [15]. Similarly our own study reported a range in injury severity,
however we continued to document significant lesions that would
highly correlate with a poor outcome. In fact almost a quarter (23%) of
those with mild NE that were imaged in our cohort had moderate-se-
vere MRI abnormalities, classified based upon the Barkovich system
[3], which would strongly predict a poor neurodevelopmental outcome
[15]. There was a variation in the rates of moderate-severe MR injury
between these studies, but this may be explained by the differences in
scoring systems utilized. Both are well validated, and highly predictive
of long-term outcome, however direct comparison has demonstrated
some variation with individual grades of injury [15].
In summary, recent evidence has consistently demonstrated that HI
brain injury is present in those with mild NE, occurring in between 20
to 40% of cases. This HI injury appears to occur in the intra-partum
period, and most frequently results in injury within the watershed re-
gions. Although there is a range in the severity of injury sustained,
significant insults that would strongly predict long-term neuro-devel-
opmental impairment have been consistently reported.
Key guidelines
• MRI is a robust predictor of long-term outcome following perinatal
asphyxia.
• Abnormalities on MRI are documented in 20 to 40% of infants with
mild NE. This includes severe lesions that are highly predictive of a
poor neuro-developmental outcome.
• Most HI injury in mild NE occurs during the intra-partum period.
• Injury in the Watershed is the predominant pattern in infants with
mild NE.
Future directions
• The development of additional neuro-imaging cohorts of infants
with mild NE is required. This data is necessary to determine if there
are specific risk factors (clinical or biochemical) associated with
injury among this population, to aid in differentiating those with
mild NE that will develop significant injury.
• Determine if neuro-protective strategies, such as therapeutic hy-
pothermia, impact on the incidence, or severity, of brain injury in
infants with mild NE.
78
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Early Human Development 120 (2018) 75–79
Conflict of interest statement
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant fi-
nancial support for this work that could have influenced its outcome.
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Corresponding author at: Department of Neonatology, Cork University Maternity Hospital, Wilton, Cork, Ireland.
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⁎
Brian H. Walsha,b, , Terrie E. Indera
a
Department of Pediatric Newborn Medicine, Brigham and Women's
Hospital, 75 Francis St, Boston, MA 02115, USA
b
Department of Neonatology, Cork University Maternity Hospital, Cork,
Ireland
E-mail address: Bhwalsh@bwh.harvard.edu