Early Diagnosis of Minor Brain Damage in Infancy : The Complementary

Nature of Clinical and Radiological Findings

Claudine Amiel-Tison
Neoreviews 2012;13;e527
DOI: 10.1542/neo.13-9-e527

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 Article developmental outcomes

Early Diagnosis of Minor Brain Damage

in Infancy: The Complementary Nature of Clinical and
Radiological Findings
Claudine Amiel-Tison, MD
Abstract
The goal of this article is to present the complementarity of clinical and radiological
Author Disclosure ndings for early diagnosis of minor brain damage in infancy. The pediatric commun-
Dr Amiel-Tison has itys historical lack of condence in the ability to identify minor brain damage early in
disclosed no financial life by neurological signs and symptoms is discussed. As a result, there has been exces-
relationships relevant sive condence in the capacity of imaging from ultrasound to MRI. This article sup-
ports a strategy of correlating the clinical approach with results from imaging studies to
to this article. This
increase our ability to identify infants with minor and moderate impairments. This ap-
commentary does not proach allows prospective follow-up and intervention for these children, who often are
contain a discussion of not identied early.
an unapproved/
investigative use of
a commercial product/ From the Pre-Imaging Period to the Present: A Historical Perspective
device. When recalling the pre-imaging period, one gets the sense of being considered, at best,
a Neolithic pioneer, reading mute astonishment in the eyes of young neonatologists. How-
ever, when neuroimaging was rst introduced, the eld of neonatal neurology was not
starting from zero. Clinical-pathologic methods had brilliantly deciphered the main types
of brain damage of perinatal origin: gross examination of xed brain slices under adequate
natural light allowed conrmation of the value of clinical signs in every severe case. In the
1960s, we already knew a lot about the evolution of periventricular leukomalacia. The as-
sociation prematurity / apneic spells / repeated episodes of bradycardia had been iden-
tied as a major risk factor for cerebral palsy (CP), so the outcome in survivors was
already predictable.
Ultrasound imaging at the bedside became available in NICUs in the early 1980s and
was immediately perceived as a historical landmark in the eld of perinatal and developmen-
tal neurology. (1) At that time, ultrasound imaging was already predictive of severe CP,
even if the quality of images was not what it is today. As a consequence, the tendency
in NICUs in the 1980s was often to give too much credit to ultrasound ndings, and
the conclusion of neonatal charts at discharge was too often ultrasound imaging within
normal limits, no indication for follow-up.
When standardized clinical assessments became available for young infants and pre-
school children, (2) there was increasing evidence that minor neuromotor impairments
without signicant gross motor consequences could be identied clinically. (3) Therefore,
the proposal at that time was to take into account the conjunction of a normal clinical as-
sessment and normal ultrasound imaging to better predict a normal outcome. Later, when
conventional MRI became available, prediction was rened, making it possible to assess the
degree of myelination of the posterior limb of the internal capsule, which correlated well
with motor dysfunction. However, radiologists had to admit that subtle white matter injury
(WMI) remained difcult to identify. One could read in
some position papers and general reviews that radiology
was not a microscope, and clinicians were still entitled to pre-
Abbreviations tend that, in cases of subtle WMI, their clinical assessment
CP: cerebral palsy was sometimes more predictive than imaging.
DTI: diffusion tensor imaging The next step in imaging advances came more recently
ELBW: extremely low birthweight with the use of diffusion tensor imaging (DTI). This tech-
WMI: white matter injury nique provides information about white matter structures
in vivo. (4) Identication of impaired connections in the

University Paris V, Paris, France.

NeoReviews Vol.13 No.9 September 2012 e527

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developmental outcomes minor brain damage
associative tissue is now possible with DTI and allows
clinical correlations with ndings demonstrated in adoles-
cence. (5) Damage in white matter connections predicts
not only motor outcome in high-risk newborn infants
but also associated dysfunctions in all domains of cerebral
function. Mapping normal white matter is the exciting
goal of the Human Connectome Project. (6) As a conse-
quence, clinicians now must demonstrate that they are
able to keep up with these dazzling advances. Debates be-
tween clinicians and radiologists, during these past decades
has had a stimulating effect on advances in their respective
elds. De Vries and coworkers proposed that we unravel
the myth that CP cannot be predicted by neuro-imaging
in neonates, (7) and they were right. However, when fo-
cusing on subtle damage, the predictive value of various
approaches must be reconsidered once again.
Positive Effects of Clinical-Radiologic
Correlations: A Few Examples
Hesitation to Predict on Clinical Grounds
in Cases of Asymmetrical Passive Tone in
the Limbs
The clinical spectrum of mild neurological and cranial im-
pairments is now reasonably well identied with various
types of assessment; good correlations with late outcome
have conrmed the usefulness of the clinical approach. (8)
However, in the past, clinicians were anxious that they
might either overdiagnose or miss mild signs and symp-
toms. Ultrasound imaging in the early 1980s helped clini-
cians in this dilemma. For instance, does a mild asymmetry
in passive tone in limbs constitute a reliable clue, even
when values are within normal limits on both sides? As
an example (9), a 28 weeks postmenstrual age newborn
infant who was born abroad came back to France after dis-
charge from the NICU; outpatient follow-up was initiated
before neonatal imaging information could be transmit-
ted. From 0 to 3 months corrected age, asymmetrical
passive tone in the limbs became apparent: relaxation
in the upper and later in the lower limbs was better
on the left side, although it was within the normal range
on both sides. At this time, imaging data collected in the
neonatal period were compared with clinical ndings:
a mild asymmetry of lateral ventricle size was already
present at the time of discharge: mild periventricular
cerebral atrophy on the left side was therefore the ex-
planation for insufcient relaxation in both upper and
lower limbs on the right side, although remaining within
the normal range. Later, this passive tone asymmetry
persisted, and mild disability was observed on the right
side, responsible for forced left-handedness. From this
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point, when repeatedly found at each assessment, those
ndings were considered a signicant instead of an in-
signicant variation from normal.
Warning to clinicians: because these clinical signs are
subtle, always perform the clinical assessment before
looking at imaging studies.
Hesitation on Radiologic Grounds in Case of
Asymmetry of Ventricular Size
Radiologists went through comparable hesitations con-
cerning the value of mild asymmetry in the size of the
lateral ventricles. They often consider such ndings com-
mon individual variation without signicance. Data ob-
tained in a study based on conventional MRI in 225
children with normal clinical ndings clearly showed that
asymmetry in size of lateral ventricles without other ra-
diologic signs is indeed a rare nding (1 in 225). (10)
Therefore such an anomaly should always be interpreted
in conjunction with passive tone in the limbs, before be-
ing considered as nonsignicant.
Warning to radiologists: before concluding that an
individual variation is without significance, always dis-
cuss with clinicians in order to carefully correlate
clinical findings and imaging findings.
Potential Misleading Effects of Unequal
Quality of Data Collection
Dealing with minor and moderate signs, the highest pos-
sible level of accuracy for each type of approach, clinical
and radiological, is indispensable. However, except in a
few university medical centers around the world, it is not
common to nd high interest in developmental neurology
combined with the most sophisticated radiologic techni-
ques. As an example, research data of Skranes et al (5)
on very low birthweight infants assessed at 15 to 19 years
of age with both DTI and neuropsychological assessment
are a model because of a comparable degree of accuracy
in both clinical and radiologic data. Such an approach
should now be introduced as routine and be reliable if,
and only if, methodological guidelines are respected.
The frustration resulting from unequal reliability in
data collection was the theme of a letter to the editor
(11) after a seminal paper by Inder et al on volumetric
MRI techniques. (12) My claim in 2005 for using

standardized clinical assessment to be able to compete
with imaging data is still justied. There is nothing at
all offensive in asking the pediatric community to be as
accurate as possible to improve the value of clinical-
radiologic correlations. The type of clinical assessment
used must be specied, instead of mentioning physical
assessment without precision about the method and
content of such assessment. Being too time-consuming
is the usual excuse for not performing a standardized as-
sessment either in research or in routine. This raises an
interesting question: does it take more time to perform
a standardized assessment than a nonstandardized one?
It is likely the opposite, given that standardized methods
usually focus on the most meaningful observations ac-
cording to their physiopathologic correlates.
Although MRI may not be available in every institu-
tion, even in developed countries, such a lack of resources
does not seem at present to be the main cause of frustra-
tion for clinicians; it is more that radiologists often do not
follow consensual technical guidelines strictly enough to
obtain good-quality imaging and allow for correct inter-
pretation of imaging ndings. (13)(14) Ideally, acrimoni-
ous claims concerning the respective predictive value of
clinical and radiologic data would vanish, to the great
benet of children with developmental disabilities. At
present, both subtle neurologic impairments and subtle
structural changes can be identied early, leading to ap-
propriate interventions at each step during childhood and
adolescence.
Insufficient Application of Neurologic
Assessment in the Term and Late Preterm
Population
Recent recommendations of the American Academy of
Pediatrics advocate systematic repeated neurological as-
sessments for every full-term newborn as part of best
practices. (15) Those recommendations often provoke
resistance and negative comments such as too long to
perform, therefore too expensive, meaningless because
of brain immaturity at this stage of maturation, useless
because the effectiveness of early intervention is not yet
evidence based. We are pleading elsewhere (16) in favor
of universal application of neurologic assessment for the
sake of the family as well as of medical staff. Several types
of assessment are well described in the literature; (17)
(18)(19) a wider application is therefore possible in any
country because it does not require any equipment. With
Julie Gosselin, I proposed a clinical assessment to follow
infants up to age 6 years (8) with a single tool adapted to
be used throughout infancy and childhood. Providing
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developmental outcomes minor brain damage
simple and precise instructions, we tried to avoid pitfalls
linked to oversimplication as well as unnecessary so-
phistication. Using a categorization of neurologic signs
observed at the corrected age of 2 years allows dening
a spectrum of neurological impairments. As demon-
strated with various at-risk populations, such a categori-
zation provides a short-term evaluation of perinatal
outcome, helping us to focus on the infants who need
long-term follow-up, even when not considered initially
at risk for brain damage. (20)(21) Implementation of
such a systematic neurologic assessment into the rst
2 years after birth would be in agreement with a recent
report from a British working group concerned with
a more accurate denition of health status at age 2 years
as a perinatal outcome. (22)
Systematic screening is even more important for the
late preterm population, too often assimilated into the
low-risk term population. (23) In fact, in agreement with
recent papers, Simard et al (21) found a high rate of children
underperforming on developmental tests; developmental
scores were signicantly correlated with neurologic status.
The designation A new diseasethe late preterm infant
(24) is therefore misleading and reects a dramatic neglect
of this underprivileged population. (25) Such a policy,
maintained over the past three decades, has been the con-
sequence of the priority put on the extremely low birth-
weight infants (ELBW) population.
Specific Requirements For the Assessment of
the Extremely Low Birthweight Population
Although the neurodevelopmental outcome may be within
normal limits in this population, many of these infants will
have neurodevelopmental disabilities later on, ranging from
minor to severe. Signs and symptoms observed since 40
weeks corrected age are often not clustered as they usually
are in more mature newborn infants. Clinicians are often
puzzled, uncertain about signs of dysregulation in the au-
tonomic nervous system and unable to classify properly the
abnormalities observed. Later, their developmental prole
often differs from the typical pattern.
The choice of the most appropriate methodology to
assess these children is still debated. (16) In the neonatal
period, two lines of research are particularly adapted to
ELBW infants. One is the Prechtls Assessment of General
Movements, (26) based on observation of spontaneous mo-
tor activity. The other, the Assessment of Preterm Infants
Behavior, was developed by Als, (27) based on observation
of the behavioral subsystems in interaction with each other
and with the environment. However, both assessments
need certication and are time-consuming and thus
NeoReviews Vol.13 No.9 September 2012 e529
developmental outcomes minor brain damage

are used more in research than in routine clinical

assessments.
Concerning the evaluation of neuromotor function in
infancy, a systematic review of available methods aiming
to evaluate their feasibility and predictive value for devel-
opmental outcome has recently been published. (18) The
authors concluded that the best prediction is achieved
when multiple, complementary clinical tools are used:
a good combination is medical history including achieved
milestones, physical and neurological examination, a spe-
cic assessment of the quality of motor behavior and re-
sults of neuroimaging such as ultrasound or magnetic
resonance imaging.
Although everybody agrees with this proposal, some
frustrations persist with three challenges remaining
unresolved:
Figure 1. Persephone supervising Sisyphus pushing his rock in
1. Better identication and understanding of signs of
the Underworld. Side A of an Attic black-figure amphora,
central nervous system dysregulation are required so
ca.530 BC. From Vulci Public Domain. Courtesy of Bibi
that they can be used as early markers of late emergent Saint-Pol, Wikipedia.
neurodevelopmental disabilities and be correlated
with structural changes detected with DTI imaging.
for pediatricians. Nevertheless, this does not mean that
Such markers should be included in a comprehensive
they should give up attempting to determine the most
clinical instrument that could be routinely applied to
appropriate intervention program because functional
the whole population of ELBW, without certication.
consequences remain the central preoccupation of both
2. More accurate markers of central visual impairment
the family and the medical team. The clinician must re-
are required because these decits are overrepresented
main the coordinator of all investigations and organize
in this population and may signicantly interfere with
at each step the best adapted intervention throughout
normal functioning as reported by Fazzi in this issue.
childhood.
(28) These markers should be used in systematic
After each methodological advance, clinical-radiologic
screening from the neonatal period on.
correlations will need to be established again. As sug-
3. Continuity in the evaluation approach in the course of
gested by Albert Camus, (29) we may imagine Sisyphus
follow-up is required because any change of the test-
happy, the rock is his own fate. However, Sisyphus,
ing method during childhood is known to lead to a de-
happy or not, was ghting alone, under Persephones
crease in validity and misinterpretation of early signs.
supervision (Fig 1). This is not the case concerning
Such methodologic continuity should also improve
follow-up studies: salvation is collaborative, the same
our understanding of the link between neurologic
stone and the same mountain for every actor of the
ndings and the functional trajectory in every domain
play.
of cerebral function.

Conclusions
At present, no case of severe perinatal brain damage American Board of Pediatrics Neonatal-Perinatal
should be allowed to escape clinical and radiologic Content Specifications
screening. However, more research is needed to improve Know the indications for and limitations of
the identication of minor and moderate brain damage. various neuroimaging studies and be able
Radiologists are achieving remarkable advances, and it is to recognize normal and abnormal
not unreasonable to expect even more accuracy in the structures and changes during
coming years, and therefore an increasing ability to iden- development and growth.
Know how a newborn infants posture,
tify more subtle structural changes in the white matter of spontaneous activity, and elicited movements are influenced
very low birthweight infants. In the era of molecular ra- by postmenstrual age and neurologic status.
diology, the challenge will become even more difcult

e530 NeoReviews Vol.13 No.9 September 2012

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 Early Diagnosis of Minor Brain Damage in Infancy : The Complementary
Nature of Clinical and Radiological Findings
Claudine Amiel-Tison
Neoreviews 2012;13;e527
DOI: 10.1542/neo.13-9-e527

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