NeoReviews October2007

educational perspectives
Portfolios: The Next

Assessment Tool in
Medical Education?
Susan Izatt, MD*
Introduction
Author Disclosure
Dr Izatt did not disclose any
financial relationships relevant to
this article.
Medical education is undergoing significant change at all levels. Selfdirected learning and reflection are
becoming essential ingredients of
both graduate medical training and
postgraduate professional development. Recognition is growing for the
need to incorporate the concepts of
andragogy into physician education,
concepts emphasizing that adult
learners are self-directed and take responsibility for their own educational
choices. The demonstration of competency for assessment of the individual and the educational program has
received increased attention in the
Accreditation Council for Graduate
Medical Education (ACGME) Outcome Project. (1) Assessment and
documentation of self-directed
learning, reflection, and competency
are more difficult than traditional
methods that have included standardized testing and conference attendance. The portfolio has been advocated as a tool for collecting and
presenting these elements of learning
at all levels of medical training.
What is a Portfolio?
Butler (2) succinctly defines a portfolio as a collection of evidence that is
gathered together to show a persons
learning journey over time and to
demonstrate their abilities. Missing
from this definition is self-reflection,
a component that several authors, including Rees, (3) believe is essential
*Assistant Professor of Pediatrics, Division of
Neonatology, Duke University Medical Center,
Durham, NC.
to a portfolio. A portfolio may be

paper-based or electronic and serves
as a coherent collection of documents chosen by the individual
learner to fit the specific purpose of
the portfolio.
Several authors have attempted to
describe different types of portfolios.
Smith and Tillema (4) describe four
different portfolio types that are defined according to purpose and setting of use. The purpose of a portfolio may be to assist with promotion
or with learning. The background
may be to fulfill external requirements or for self-learning. The dossier
portfolio is a collection of mandated
works that is required for entry into a
profession, while a training portfolio
is a set of mandatory works assembled for learning during training.
The reflective portfolio is a personal
selection of works that reflects an individuals progress to assist with promotion, contrasting with the developmental portfolio, which features a
selection of works to allow reflection
and self-learning.
Another description of portfolios
in educational training is provided by
Zeichner and Wray. (5) In the education field, teachers in training use
portfolios to make the activity of
learning visible. A learning portfolio
begins as a collection of educational
products, including personal learning philosophies, learning theories,
sample curricula, evaluative tools,
and individual assessment that reflects the progress of the learner during training. When the learner needs
to demonstrate proficiency to obtain
an initial teaching license, a credentialing portfolio is created that includes works that demonstrate profiNeoReviews Vol.8 No.10 October 2007 e405
ciency of the teaching standards

defined by the state. Some educators
may develop a showcase portfolio to
contain evidence of their best works
for recruitment and promotion.
Portfolios in Medicine
As the focus in medical education
shifts to the demonstration of competence and lifelong learning, portfolios are being piloted as an assessment tool in a manner analogous to
the education field. (6)(7)(8) The
power of the portfolio lies in its emphasis on reflection, which distinguishes it from a simple dossier of
evidence. (3) Reflection allows physicians at all stages of training to learn
from their actions and promotes continued review of the literature to
keep up to date.
Individual graduate medical education programs have incorporated
either traditional paper-based portfolios or e-portfolios as assessment
tools. The psychiatry program within
the University of Arkansas for Medical Sciences introduced a case-based
portfolio as an additional approach
to assess residents. (9) The paperbased showcase portfolio contained
cases and documentation selected by
the resident that best represented 13
skills believed to be essential for a
competent psychiatrist. These skills
were derived from the Residency Review Committees objectives. The
Royal College of Paediatrics and
Child Health introduced a paperbased learning or training portfolio
as a method of assessing six domains
of competence, including clinical,
communication, teaching and learning, ethics and attitudes, management and evaluation, and creation of
evidence. (10) Clinic letters, handouts, and ethical submissions as well
as evaluations, letters, and attendance certificates were included for
assessment of learning and progress
in specific domains to allow ime406 NeoReviews Vol.8 No.10 October 2007
proved feedback. In 2001, the Department of Surgery at the Medical

College of Wisconsin developed a
case-based learning portfolio to allow
resident documentation of cases representing various disease states and
encourage reflection on practice.
(11) A template was completed
monthly that included the case history, diagnosis, management, treatment, reflections on lessons learned
from the case, and review of two
articles. Although diverse, all three
portfolios have been used as educational tools for assessment and feedback.
The content presently found in
the learning or training portfolios of
graduate medical learners varies from
institution to institution. Examples
of potential evidence that may be
included in portfolio used for resident learner assessment are outlined
in the Table. Carraccio and Englander (6) describe an evaluation
portfolio that is broken down further
into the assessment of the six
ACGME core competencies.
The Effectiveness of
Portfolios in Medicine
Limited data are available on the validity and reliability of portfolios as
assessment tools in postgraduate
medical education. Portfolios are ascribed high face validity because the
tool appears appropriate to the test
situation of the resident learners.
However, reliability remains an area
of weakness for a tool that is proposed for summative evaluation and
high-stakes decision making. In separate small studies, examination of
inter-rater reliability revealed interrater correlation coefficients to be
below the accepted value of 0.8.
(10)(12) Interassessment correlation
also was found to be weak in two
small studies. (10)(13) It has been
proposed that reliability could be improved if portfolios were standard-
Sample
Content for
Portfolios in
Graduate Medical
Training
Table.
Evaluations
Rotation-specific evaluations
360-degree evaluations
Peer evaluations
Self-assessment
Patient and Procedure Logs

Procedural Competency
Documentation
Certificates
Neonatal Resuscitation Program

Pediatric Advanced Life Support
Examination Scores
Inservice board examination

Step Exam scores
Conference Attendance
Presentations
Case presentations
Journal club
Institutional conferences
National conferences
Projects
QA project
Senior research project
Individual Learning Plan

Reflections
Individual patient
Critical event
Ethical challenge
Learning and growth
Sample Evidence Selected by

Medical Learner
ized, the residents educated about

the use of the portfolio, criteria for
scoring the portfolio were developed, and the evaluators were
trained. Driessen and associates (14)
have suggested that use of strategies

from qualitative research, including
triangulation, prolonged engagement, and member checking, would
allow credibility and dependability of
portfolio assessment.
Portfolios are believed to be effective tools for evaluating skills and attitudes, areas that traditionally have
been difficult to evaluate. Examining
the ability of the portfolio to measure
the six ACGME core competencies,
Jarvis and colleagues (12) found evidence of patient care, professionalism, interpersonal and communication skills, medical knowledge, and
system-based practice. The lack of
evidence of practice-based learning
was attributed to the development of
the portfolio prior to the introduction of the core competencies.
The Evolution of the

Electronic Portfolio
The structure of the portfolios and
the role of reflection within them are
not consistent due to the present
paucity of standardized tools. Existing computer-based platforms, such
as Trivantis Lectora and TaskStream, allow individuals and programs to create portfolios by providing templates, but they do not
contain standardized content specific
to established guidelines. PediaLink
was established by the American
Academy of Pediatrics (AAP) as an
online learning center to promote
and document self-learning for both
pediatric residents and pediatricians
and functions perhaps as a developmental portfolio. (15) The structure
of PediaLink is adapted from
Schons model of reflection-inaction and reflection-on-action,
wherein a surprise causes the practitioner to reflect and seek additional
information to assist with selflearning. (16) The Individualized
Learning
Plan
found
within
PediaLink offers a structured sys-
tem for documenting learning efforts

in residency and practice. The
PediaLink site can be accessed
at:
https://www.pedialink.org/
index.cfm.
In 2006, the ACGME began the
development of an electronic webbased resident portfolio. Their mission to improve health care by assessing and advancing the quality of
residents education through accreditation has led to the ACGME Outcome Project, which includes the
need to improve the effectiveness of
the evaluation of the six core competencies. (1) Further, it has been
recognized that domain-based evaluation rather than norm-based evaluation is necessary to assess the
achievement of competency of medical learners. The ACGME learning
portfolio is built on the ideals of experience, reflection, learning, and assessment.
A news release from the ACGME
in May 2007 outlines the proposed
learning portfolio:
The ACGME Learning Portfolio
is an interactive, web-based development tool that residents can use
through out their residencies to
record and organize their learning,
track their progress against defined
learning objectives, reflect on their
learning experiences, and receive
feedback on their skills as physicians.
Used throughout residency education, the portfolio will provide residents with a collection of evidence
about their professional competence
and support their transition into private practice. (17)
A broad vision is outlined for the
ACGME learning portfolio. (18) It is
described not only as a learning tool
for residents, but as a storehouse for
documentation needed by licensing
groups and certification boards, fitting the definition of both a learning
portfolio and a credentialing portfolio.
The portfolio is envisioned to assist
the program director both with improved assessment of the resident

and enhanced data collection for residency review committees. Issues of
connectivity
between
existing
ACGME systems are being addressed early in the design process.
Alpha testing of the ACGME learning portfolio began in July 2007,
with the goal of broad-based utilization in 2010. Beta testing is planned
to begin in 2008, using specialty
groups to develop tools and content
that fit their specific needs.
The electronic format used by the
AAP and the ACGME portends the
future of assessment tools. Electronic
portfolios (ePortfolios) do not differ in concept from paper-based
portfolios, but reflect practical improvements, including ease of standardization. Although requiring
technologic skills for their initial development, ePortfolios allow easier
access and maintenance by the
learner. ePortfolios can contain many
pieces that serve as evidence of learning, including audio, video, and
works in electronic format. Selfreflection is an ongoing process as
the ePorfolio is developed and revised. The electronic format allows
greater portability and sharing than
traditional paper-based tools.
Both the AAP and ACGME have
incorporated the potential role of the
ePortfolio beyond graduate medical
education into its underlying design.
The emphasis on lifelong learning
and reflection throughout a medical
career poses assessment challenges
for recertification and promotion.
The United Kingdom already requires its consultants to develop a
portfolio to assist in the recertification process. (19) PediaLink represents an existing repository for
practicing pediatricians to collect
continuing medical education information, professional data, individualized learning plans, and reflectionNeoReviews Vol.8 No.10 October 2007 e407
on-action practice changes to address

this new evaluative approach. Academic medical centers are beginning
to use portfolios in both the paper
and electronic forms for promotion,
although the portfolios may be more
dossiers of evidence, lacking in reflection. The ACGME is working
with other agencies to extend the
use of the proposed electronic
learning portfolio beyond medical
training.
Conclusion
Quality health care relies on medical
professionals who have a solid educational cornerstone that is maintained
through lifelong learning and reflection. The public demands competency of those who provide health
care. The assessment of such characteristics through all stages of medical
training and practice is essential but
difficult. The portfolio offers one potential tool to help with this process.
References
1. The ACGME Outcome Project. Available
at:
http://www.acgme.org/outcome/.
Accessed July 25, 2007
2. Butler P. A Review of the Literature on
Portfolios and Electronic Portfolios. 2006.
Available
at:
http://eduforge.org/
docman/view.php/176/1111/ePortfolio
e408 NeoReviews Vol.8 No.10 October 2007
%20Project%20Research.pdf. Accessed July

25, 2007
3. Rees C. The use (and abuse) of the term
portfolio. Med Educ. 2005;39:436 437
4. Smith K, Tillema H. Clarifying different
types of portfolio use. Assessment & Evaluation in Higher Education. 2003;28:
625 648
5. Zeichner K, Wray S. The teaching portfolio in US teacher education programs:
what we know and what we need to know.
Teaching and Teacher Education. 2001;17:
613 621
6. Carraccio C, Englander R. Evaluating
competence using a portfolio: a literature
review and web-based application to the
ACGME competencies. Teach Learn Med.
2004;16:381387
7. Ruiz JG, van Zuilen MH, Katz A, Milanez M, Tiberius RG. ePortfolios in graduate medical education. In: Jafari A, Kauf C,
eds. Handbook of Research on ePortfolios.
Hershey, Pa: Idea Group, Inc; 2006:
283291
8. Snadden D, Thomas M. The use of portfolio learning in medical education. Med
Teach. 1998;20:192199
9. OSullivan PS, Cogbill KK, McClain T,
Reckase MD, Clardy JA. Portfolios as a
novel approach for residency evaluation.
Acad Psychiatry. 2002;26:173179
10. Melville C, Rees M, Brookfied D,
Anderson J. Portfolios for assessment of
paediatric specialist registrars. Med Educ.
2005;38:11171125
11. Webb TP, Aprahamian C, Weigelt JA,
Brasel KJ. The surgical learning and instructional portfolio (SLIP) as a self-assessment
educational tool demonstrating practicebased learning. Curr Surg. 2006;63:
444 447
12. Jarvis RM, OSullivan PS, McClain T,

Clardy JA. Can one portfolio measure the
six ACGME general competencies? Acad
Psychiatry. 2004;28:190 196
13. Davis MH, Friedman Ben-David M,
Harden RM, et al. Portfolio assessment in
medical students final examinations. Med
Teach. 2001;23:357366.
14. Driessen E, van der Vleuten C, Schuwirth L, van Tartwijk, Vermunt J. The use of
qualitative research criteria for portfolio assessment as an alternative to reliability evaluation: a case study. Med Educ. 2005;39:
214 220
15. Sectish TC, Floriani V, Badat MC,
Perelman R, Bernstein HH. Continuous
professional development: raising the bar
for pediatricians. Pediatrics. 2002;110:
152156
16. Borduas F, Gagnon R, Lacoursiere Y,
Laprise R. The longitudinal case study: from
Schons model to self-directed learning.
J Contin Educ Health Prof. 2001;21:
103109
17. ACGME learning portfolio alpha testing will begin in July [news release].
Chicago, Ill: Accreditation Council for
Graduate Medical Education; May 23,
2007. http://www.acgme.org/acWebsite/
newsreleases/newsRel_5_24_07.pdf.
Accessed July 25, 2007
18. ACGME Learning Portfolio: A Professional Development Tool Experience Reflect,
Learn, Assess. Available at: http://www.
acgme.org/acWebsite/portfolio/
cbpac faq.pdf. Accessed July 25, 2007
19. Davies H, Khera N, Stroobant. Portfolios, appraisal, revalidation, and all that: a
users guide for consultants. Arch Dis Child.
2005;90:165170
Article
neurology
Injury to the Developing

Cerebellum: Mechanisms and
Consequences
Catherine Limperopoulos,
PhD,* Adre J. du Plessis,
MBChB, MPH
Author Disclosure
Drs Limperopoulos
Objectives
After completing this article, readers should be able to:
1. Describe the critical events in cerebellar development and how insults to the
developing cerebellum may cause major disruption of its developmental program.
2. Explain differences in the topography of cerebellar injury in preterm and term infants.
3. Delineate the spectrum of neurodevelopmental disabilities in survivors of early life
cerebellar injury.
and du Plessis did not

disclose any financial
relationships relevant
to this article.
Abstract
Advances in neuroimaging techniques for the in vivo study of brain development have
expanded the understanding of normal and abnormal cerebellar development in the
high-risk fetus and newborn. This, in turn, has provided new insights into the
spectrum of structural and functional consequences of injury to the developing
cerebellum. Specifically, hemorrhagic cerebellar lesions in preterm infants are associated with significant impairment of subsequent cerebellar growth as well as impaired
growth of the contralateral cerebral hemisphere. Furthermore, preterm extrauterine
life appears to inhibit cerebellar growth, even in the absence of obvious primary injury.
Recent long-term outcome studies in preterm infants who had cerebellar injury
suggest a distinct profile of pervasive neurodevelopmental deficits, with a high
prevalence of cognitive-behavioral dysfunction. The structure-function relationships
between early cerebellar injury and long-term outcome are a fertile area for future
research.
Introduction
Understanding of normal and abnormal brain development has accelerated in recent years.
Two factors facilitating these advances are the increasingly sophisticated brain imaging
techniques for in vivo study of brain development and the increased survival of young
infants from critical illness. Together, these trends have promoted insights into normal
development, mechanisms of injury, and the structural and functional consequences of
such injury. To date, both clinical and research activities have focused predominantly on
events in the supratentorial brain regions. In the preterm infant, clinical and research
activities have concentrated on lesions such as periventricular leukomalacia and germinal
matrix-intraventricular hemorrhage. In the term infant, the different insult-injury patterns
(primarily hypoxic-ischemic) in the cerebral hemispheres have attracted most of the clinical
and research attention.
However, in recent years recognition of injury to the developing cerebellum, and of the
impact of such injury on long-term outcome, has increased. A broad spectrum of insults
may injure the developing cerebellum. Because most are cerebrovascular in origin, this
review focuses on the mechanisms and sequelae of hemorrhagic and hypoxic-ischemic
injury. The vulnerability and response to injury of the developing cerebellum are inextricably linked to the developmental events unfolding during gestation, necessitating a brief
introduction to normal cerebellar development.
*Canada Research Chair in Brain and Development; Assistant Professor, Department of Neurology and Neurosurgery, School of
Physical and Occupational Therapy, and Department of Pediatrics, McGill University, Montreal, Quebec, Canada; Fetal-Neonatal
Neurology Research Group, Childrens Hospital Boston, Boston, Mass.
Senior Associate in Neurology; Director, Fetal-Neonatal Neurology Research Group, Childrens Hospital Boston; Associate
Professor of Neurology, Harvard Medical School, Boston, Mass.
NeoReviews Vol.8 No.10 October 2007 e409
neurology
cerebellar injury
Normal Development of the Cerebellum

Perhaps the most striking feature of cerebellar development is its protracted time course, which is central to
both the organs vulnerability and the developmental
repercussions of injury. Specifically, development of the
future cerebellum begins soon after neural tube closure
around 4 weeks of gestation and is not complete until
several years after birth. This prolonged developmental
program may be divided into several phases. (1)
Early differentiation of the cerebellar primordium is
directed by the isthmic organizer at the mid-hindbrain
junction, which triggers events that commit the first
rhombomere to cerebellar differentiation. (2)(3)(4) In
the late second month of gestation, the lateral aspects of
the cerebellar primordium, the future hemispheres, enlarge rapidly, followed in the third month by accelerated
growth in the midline, the future vermis. Early hemispheric development is characterized by a series of complex cellular migrations. First, cells from the primary
neuroepithelium adjacent to the fourth ventricle migrate
into the cerebellar primordium to form the future deep
nuclei and Purkinje cell layer. Following soon hereafter, a
second wave of cells migrates into the lateral rhombic
lips. Two further migrations are launched from the
rhombic lips. From the upper rhombic lip, tangential
migration over the subpial surface of the developing
cerebellar hemispheres forms the external granular layer.
From the lower rhombic lips, ventral migration forms
pontine structures, such as the precerebellar pontine and
inferior olivary nuclei. Disturbances in these rhombic lip
migrations underlie the common association between
cerebellar and brainstem malformations.
The external granular layer forms a secondary neuroepithelium of intense cellular proliferation from which
ventral migration occurs along the Bergmann glial cells
into the developing hemisphere, crossing the Purkinje
cell layer and leading to formation of the deeper internal
granular layer. Events originating in and around the
external granular layer are critical to the vulnerability of
the developing cerebellum and its response to injury.
First, the surface of the external granular layer is covered
by a dense leptomeningeal vascular plexus, which sends
perforating arteries into the cerebellar parenchyma, ultimately extending to the deep cerebellar nuclei. However,
compared with the deeper parenchyma of the cerebellum, the external granular layer is left relatively undervascularized, possibly because its vigorous cellular proliferation allows insufficient time for establishment of a
permanent capillary bed. (5) Second, developmental
events originating in the external granular cell layer occur
over an extended period from the late embryonic period
to the end of the second postnatal year. For these reasons, insults during this period may cause significant
disruption of future cerebellar development and may
underlie the often striking cerebellar growth failure following early injury.
Injury to the Developing Cerebellum

A broad spectrum of agents can injure the developing
cerebellum, ranging from viral infections, such as cytomegalovirus, to inherited disorders of metabolism, such
as disorders of peroxisomal biogenesis and glycosylation.
For reasons cited previously, insults to the developing
cerebellum have the potential not only to injure the
developing organ but also to disrupt its subsequent
developmental program. In fact, it is likely that some
lesions classified by in vivo imaging as primary dysgenetic
anomalies of the cerebellum (with a presumed genetic
origin) are, in fact, developmental disruptions due to
acquired insults. Progress in the genetics of cerebellar
development and dysgenesis has been rapid in recent
years, but discussion of these advances is beyond the
scope of this review.
Injury to the Preterm Cerebellum

Cerebellar injury is increasingly recognized as a complication of extreme premature birth (6)(7)(8)(9) and has
been described on fetal imaging. (10)(11)(12) The primary pathogenetic mechanism(s) for these lesions in the
preterm infant remains unclear, but because a hemorrhagic component usually is prominent on ultrasonography, we use the term cerebellar hemorrhagic injury
(CHI). The incidence of CHI in preterm infants is not
clear. Earlier estimates of cerebellar injury in all newborns
have ranged from 2.5% to 3.6%. (13)(14)(15)(16)(17)
In the selected population of low-birthweight infants
studied at autopsy, rates of CHI as high as 15% to 25%
have been described. (18)(19) Until recently, in vivo
rates of CHI in preterm infants have been difficult to
establish, in part due to limitations of posterior fossa
imaging techniques. Cranial ultrasonography through
the anterior fontanelle is limited in the ability to detect
posterior fossa lesions, due both to the distance traversed
by the ultrasonography beam and the echogenicity of the
tentorium and skull base. Approaches through the acoustic windows of the posterior fontanelle and mastoid
foramen have begun to overcome these limitations, providing significantly improved definition of the posterior
fossa structures and detection of lesions (Fig. 1). A recent
cranial ultrasonography study using a mastoid approach
to the posterior fossa detected CHI in 19% of extremely
low-birthweight infants (750 g), suggesting that the
neurology
Figure 1. On the left, a drawing illustrates the neonatal skull (lateral view) with the major
sutures, including the anterior fontanelle (AF) and posterior fontanelle (PF), with an
ultrasonographic transducer positioned over the mastoid fontanelle. On the right, an
ultrasonographic image of the posterior fossa obtained through the mastoid fontanelle
depicts the cerebellar hemisphere (1), the posterior vermis (2), and the fourth ventricle
(3). Drawing adapted with permission from Buckley KM, Taylor GA, Estroff JA, Barnewolt
CE, Share JC, Paltiel HJ. Use of the mastoid fontanelle for improved sonographic
visualization of the neonatal midbrain and posterior fossa. AJR Am J Roentgenol.
1997;168:10211025, by the American Roentgen Ray Society. Ultrasonography image
adapted with permission from Di Salvo DN. A new view of the neonatal brain: clinical
utility of supplemental neurologic US imaging windows. Radiographics. 2001;21:943
955, by the Radiological Society of North America.
prevalence of CHI has been underestimated in these

smallest infants. (6) The increased survival of particularly
sick extremely low-birthweight infants, more focused
posterior fossa ultrasonography approaches, and more
widespread use of magnetic resonance imaging (MRI)
have demonstrated a wide spectrum of CHI in preterm
infants.
The precise etiopathogenesis of such CHI lesions
currently is unresolved. Several different mechanisms
have been proposed, ranging from primary hemorrhage
to hemorrhagic transformation of an ischemic injury
(either arterial or venous) or a combination of these
mechanisms. Common locations for CHI in the preterm
infant include the deeper subependymal and superficial
subpial regions, corresponding to locations of the primary and secondary germinal matrices described previously. The transient nature of the germinal matrices,
together with their sparse and temporary vasculature,
may predispose to hemorrhage. Pathology studies demonstrating the frequent occurrence of microscopic hemorrhagic lesions in the external granular and molecular
layers have supported the concept of an ischemiareperfusion mechanism for hemorrhage in these undervascularized regions of the cerebellar cortex. Supporting the supposition that CHI lesions share common
mechanisms with supratentorial germinal matrixintraventricular hemorrhagic lesions is the fact that such
cerebellar injury
lesions often occur together and

share the same clinical antecedents.
The role of cerebral pressure passivity and unstable systemic hemodynamics and their effect on these
fragile cerebellar vascular structures
has not been delineated. (6) Other
mechanisms proposed for CHI injuries include dissection of blood
from the fourth ventricle into the
vermis or from the overlying subarachnoid space into the hemispheric parenchyma. (19)
Injury to the Term

Cerebellum
Hemorrhagic Injury
Cerebellar hemorrhage in the term

infant is likely due to different
pathogenetic mechanisms. In the
past, severe forms of cerebellar
hemorrhage were described in the
context of traumatic birth and severe
rhesus
isoimmunization.
(20)(21) Injury in term infants has been associated with
traumatic delivery, including breech presentation, and
prolonged labor with excessive cranial molding. Traumatic and especially instrumented deliveries may result in
severe distortion of the pliable developing cranium and
dural structures, with disruption of veins. Therefore,
tentorial or falcine lacerations are seen, often accompanied by lacerations of the vermis, in such traumatic
deliveries. Of note, the external granular layer still is
prominent, even at term gestation, and presumably remains vulnerable to the consequences of hemorrhagic
injury.
Hypoxic-ischemic Injury
In the term fetus, severe transient insults are associated
with injury converging on the thalamus, basal ganglia,
sensorimotor cortex, and brainstem. (22) Such regional
vulnerability of the term brain is believed to relate to
regional differences in perfusion, metabolic activity, and
active primary myelination. (23) More recently, involvement of the cerebellar vermis has been reported after
transient but particularly severe intrapartum insults (Figs.
2 and 3). (24) Although hypoxic-ischemic cerebellar
injury in the term fetus has been well described pathologically, it is relatively unrecognized on neuroimaging
studies. In a recent study, infants suffering severe perinatal asphyxia and dying in the early postnatal period
neurology
cerebellar injury
Figure 2. Axial view T2-weighted fast spin-echo (3555/
112) image obtained through the posterior fossa in a

5-month-old male infant who was born after uterine rupture
shows hyperintensity in the cerebellar vermis immediately
behind the fourth ventricle (arrow). Neonatal computed tomography scan performed on day 3 showed abnormal thalami
with normal cortex, whereas magnetic resonance imaging
performed on day 17 showed signal intensity abnormalities in
the thalami, hippocampus, and rolandic cortex. Reproduced
with permission from Sargent MA, Poskitt KJ, Roland EH, Hill
A, Hendson G. Cerebellar vermian atrophy after neonatal
hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol.
2004;25:1008 1015, by the American Society of Neuroradiology.
showed loss of Purkinje and eosinophilic Purkinje cells

and proliferation of Bergmann astrocytes in the absence
of cerebellar imaging abnormalities. (22) In this study,
infants undergoing MRI at a time when other brain
regions showed obvious injury (10 to 18 days after
birth) had normal-appearing cerebellar hemispheres
and vermis. Later MRI studies showed injury to the
cerebellar vermis, confined to the superior (and deeper
rather than peripheral) vermis, with rare mild injury to
the cerebellar hemispheres. (22)(23)(24)(25)(26) It is
unclear whether such vermian lesions were the result of
direct hypoxic-ischemic injury or due to remote brain
injury in the regions described previously. (22)
Structural Consequences of Injury to the

Developing Cerebellum
Advances in neuroimaging not only have allowed a more
accurate estimation of the frequency of CHI in high-risk
infants, but also have allowed for the quantitative study
of the structural consequences of CHI with follow-up
MRI. In addition, these techniques have allowed the
Figure 3. Coronal view T2-weighted fast spin-echo (6480/

96) magnetic resonance imaging of a 20-month-old boy
shows hyperintensity with volume loss in the superior cerebellar vermis (arrow). The child had thalamic edema with
normal cortex shown by neonatal computed tomography scan.
Other images in this follow-up study showed symmetric
hyperintensity of the ventrolateral thalami, posterior lentiform nuclei, and periventricular white matter extending to the
rolandic cortex but with normal cortical gray matter. Reproduced with permission from Sargent MA, Poskitt KJ, Roland
EH, Hill A, Hendson G. Cerebellar vermian atrophy after
neonatal hypoxic-ischemic encephalopathy. AJNR Am J Neuroradiol. 2004;25:1008 1015, by the American Society of
Neuroradiology.
study of growth and development in remote cerebral

projection areas of the cerebellum following neonatal
cerebellar injury and vice versa.
Cerebellar Growth Failure Following CHI in

Preterm Infants
The common location of CHI in the germinal matrix
regions, with exposure of their highly mitotic cerebellar
precursor cells to the injurious breakdown products of
extravasated blood, may underlie the striking cerebellar
hypoplasia seen on later MRI in survivors of CHI.
Johnsen and associates (8)(9) described an extensive
bilateral form of injury involving both cerebellar hemispheres and the vermis that resulted ultimately in a
pancake-like-appearing cerebellum. Such cerebellar lesions were associated with pontine hypoplasia and supratentorial parenchymal injury. They proposed a vasoocclusive injury involving both inferior cerebellar arteries
as the underlying mechanism. More recently, Limperopoulos and colleagues (27) extended the spectrum to
include unilateral hemispheric lesions, unilateral hemispheric plus vermis lesions, and bilateral hemispheric and
neurology
cerebellar injury
pratentorial lesions occurred commonly, but injury was confined to

the cerebellum in 23% of cases.
Cerebellar Development in
Preterm Infants Who Do
Not Have Obvious Neonatal
Cerebellar Injury
REMOTE EFFECTS OF PRIMARY
BRAIN INJURY. Advances in quantitative MRI not only have allowed
Figure 4. Preterm cerebellar hemorrhagic injury. Follow-up brain magnetic resonance delineation of cerebellar growth afimaging (coronal SPGR T1-weighted) of infants who had isolated cerebellar hemorrhagic ter CHI in preterm infants, but also
injury on neonatal cranial ultrasonography. A. Complete absence of the left cerebellar have provided important insights
hemisphere with preservation of the right cerebellar hemisphere and vermis. B. Absence
into the effects of cerebellar injury
of the inferior cerebellar vermis and inferior portions of both cerebellar hemispheres. C.
on contralateral supratentorial paNear-total cerebellar destruction with only a small amount of superior cerebellar vermis
present. Reproduced with permission from Limperopoulos C, Bassan H, Gauvreau K, et al. renchymal growth and developDoes cerebellar injury in preterm infants contribute to the high prevalence of long-term ment. Conversely, supratentorial
cognitive, learning, and behavioral disability in survivors? Pediatrics. In press, by the lesions such as periventricular
leukomalacia or periventricular
American Academy of Pediatrics.
hemorrhagic infarction have been
associated with impaired growth
vermis lesions, the latter further categorized by severity
and development of the contralateral cerebellar hemiinto partial inferomedial and profound near-complete
sphere, even in the absence of obvious cerebellar injury
injury to the cerebellum (Fig. 4).
on MRI studies in the neonatal period. Applying adSeveral recent studies have described an important
vanced three-dimensional volumetric and MRI parcellarelationship between cerebellar hemorrhagic injury and
tion techniques, the effect of trophic withdrawal on
subsequent impairment of unilateral or bilateral growth
contralateral transtentorial brain development has been
and developmental impairment of the cerebellum. In
documented as significant decreases in the volumetric
fact, it has been suggested that some lesions in the
growth of remote projection areas. Unilateral cerebral
cerebellar hypoplasia/aplasia spectrum might originate
parenchymal injury was associated with a significantly
in an acquired cerebrovascular insult. (7)(28) An extendecreased volume of the apparently uninjured consive and symmetric form of cerebellar injury, usually
tralateral cerebral hemisphere at follow-up MRI study;
associated with pontine hypoplasia and supratentorial
(6) unilateral primary CHI was associated with conparenchymal injury, has been described. (7)(8)(9)(29)
tralateral cerebral hemispheric volumetric growth imIn recent years, a clinically silent and less extensive form
pairment.
of cerebellar hemorrhagic injury, often without supratenBeyond this diaschisis effect on overall hemispheric
torial hemorrhage, has been described. (6)(17) In a
growth, parcellation techniques have allowed the identi5-year retrospective review of preterm infants, CHI was
fication of specific supratentorial projection areas affected
identified in 35 infants via mastoid foramen ultrasonogby trophic withdrawal. Of note, the effects of trophic
raphy views of the posterior fossa. The follow-up MRI
withdrawal from contralateral transtentorial centers is
studies in the affected infants showed a range of cerebelapparent as early as term corrected age, a reflection of the
lar injury that extended from a mild and more prevalent
rapid rate of cerebellar growth during the third trimester.
form (71%) that was largely focal and unilateral to a more
These quantitative regional MRI techniques are prodiffuse and extensive form (9%) that involved both cereviding important insights into the highly integrated
bellar hemispheres and the vermis. In the more extensive
anatomic and functional interactions between supraform of injury, the lesions ranged from partial inferotentorial and cerebellar centers and will provide powmedial defects to near-complete cerebellar destruction,
erful tools for delineating the structural substrate for
similar to that described previously. (7)(9) In the study
later functional disabilities in infants who suffer cereby Limperopoulos and associates, (6) concomitant subellar injury.
neurology
cerebellar injury
CEREBELLAR DEVELOPMENT IN PRETERM INFANTS

WHO DO NOT HAVE PRIMARY BRAIN INJURY. In addition
to the consequences of obvious prematurity-related injury to the development of the developing brain, recent
studies have shown impaired cerebellar growth in survivors of prematurity, even in the absence of obvious brain
injury by early MRI. Former preterm infants studied
during adolescence (30)(31) showed impaired lateral
cerebellar volumetric growth, which was associated with
decreased cerebral white matter volumes. In a subsequent study, (32) the effect of premature extrauterine life
per se on cerebellar growth was addressed using the same
quantitative MRI techniques. These studies confirmed
the rapid rate of cerebellar growth in the third trimester
by comparing cerebellar volumes soon after preterm
birth with the volumes measured in term infants. Of
particular interest was the finding that premature extrauterine life appeared to be associated with significantly
smaller cerebellar volumes as early as term corrected age
compared with term-born normal infants, even in the
absence of demonstrable MRI evidence of brain injury.
(32) These findings suggest either the presence of noxious extrauterine factors or withdrawal of growthpromoting intrauterine factors during the extrauterine
third trimester in preterm infants. Such possibilities provide important targets for future research into the causes
and sequelae of cerebellar growth failure in preterm
infants.
Functional Consequences of Injury to the

Developing Cerebellum
The Cerebellum and Higher-order Cognitive
and Behavioral Function
Until recently, the cerebellum was considered a fundamental component of the motor system, with very little,
if any, cognitive-affective function. This traditionally
held concept of cerebellar function has been challenged
by a number of recent anatomic, physiologic, and functional neuroimaging studies that suggest a significant
role for the cerebellum in higher-order cerebral functions. (33)(34)(35)(36)(37)(38)(39) In these studies,
the clinical features of a distinct cerebellar cognitive
affective syndrome have been described, which includes
core elements of executive, spatial, language, and affective disturbances. (34) Key elements of the syndrome
include disorders of executive function, visual-spatial
organization, and memory as well as personality changes
involving disinhibited, inappropriate behavior and blunting of affect. Specific language deficits also have been
described. (33)(34)(35)(40) Although the cerebellar
cognitive-affective syndrome originally was described in
adults, children who have cerebellar lesions, such as

surgical excision of tumors, have demonstrated similar
higher-order deficits, including severe language impairment and disorders of visual-spatial function and working memory. (41)(42)(43)(44) However, the impact of
cerebellar injury in the preterm and term infant, particularly its nonmotor sequelae, remains poorly described.
The cerebellum has been implicated in childhoodonset disorders such as attention-deficit/hyperactivity
disorder and infantile autism. Specifically, the vermis
and, in particular, specific lobules of the vermis have been
implicated in these disorders. (45)(46)(47)(48)(49)(50)
These adult, childhood, and developmental data suggest
that the cerebellum not only plays an important role in
higher-order function in more mature individuals but
also is critical for the development of normal speech,
language, and social skills.
Functional Outcome of Preterm Cerebellar

Injury
In recent years, the appreciation that neurodevelopmental deficits in survivors of prematurity extend well beyond
impairments in motor function, including spastic cerebral palsy, has been demonstrated in a number of studies.
In fact, data suggest that up to 50% of preterm infants
reaching school age have significant deficits in cognitive,
behavioral, and learning skills. To date, the structurefunction underpinnings of these deficits have been examined largely in the context of supratentorial injury, with
the role of the cerebellum being relatively underexplored. Data for neurodevelopmental and particularly
cognitive outcome in survivors of cerebellar hemorrhagic
injury have been limited and controversial. Outcomes
have ranged from favorable to significant neurodevelopmental impairment. (8)(9)(20)(21)(51)(52) These disparate outcome data likely reflect limitations of small
sample size, diverse gestational age, and age at outcome
testing as well as the lack of standardized measures focusing on cognitive and behavioral outcomes. Allin and
colleagues (30)(31) have described an association between impaired cerebellar growth and cognitive impairment in former preterm infants studied during adolescence, who exhibited impaired executive, visual-spatial,
and language function.
With regard to cerebellar injury in the preterm population, previous studies had focused on a subgroup of
infants who had particularly severe cerebellar injury associated with cerebral parenchymal injury. (9) Not surprisingly, these children at follow-up demonstrated severe
neurologic dysfunction, with microcephaly, spastic and
hypotonic cerebral palsy, ataxia, and seizures. A more
neurology
recent case-controlled study, in which 35 infants who

had isolated cerebellar hemorrhagic injury were compared with gestational and postnatal age-matched controls, circumvented some of the earlier limitations. (27)
In this study, isolated cerebellar hemorrhagic injury in
the preterm infant was associated with a significant prevalence of pervasive neurodevelopmental disabilities and
functional limitation compared with age-matched controls. Although motor deficits were noted in the former
preterm infants who had cerebellar injury, the magnitude
of the deficits was relatively less severe than that seen in
older individuals who had cerebellar injury. Common
motor deficits included hypotonia and oculomotor deficits and abnormal gait patterns. Higher-order deficits,
including positive autism screening, were particularly
prevalent in the children and severe in cases involving the
cerebellar vermis. Of interest, when the outcome in
infants who had isolated cerebellar hemorrhagic injury
was compared with that in 16 former preterm infants in
whom cerebellar hemorrhagic injury occurred in association with supratentorial parenchymal injury, there were
no significant differences in cognitive, language, and
social function between the two groups, although those
who had associated cerebral injury had greater motor
deficits.
The high prevalence of cognitive-behavioral dysfunction in former preterm children, their predilection for
impaired cerebellar growth, and the emerging awareness
of the cerebellums role in higher-order brain function
raise important questions about the impact of cerebellar
developmental impairment in the cognitive and learning
difficulties seen in survivors of prematurity.
Functional Outcome of Term Cerebellar Injury

The neurodevelopmental consequences of cerebellar injury in term infants are more difficult to delineate. Hemorrhagic injury in the term infant has, at least in the past,
been associated with high acute mortality and significant
neurologic deficits, including hypotonia, truncal ataxia,
intention tremor, and nystagmus. Delineation of the
functional sequelae of superior cerebellar vermian injury
following perinatal asphyxia in term infants should
present a more difficult challenge because of the severity
of associated injury to supratentorial structures. Significant cognitive delay also has been described in this population, particularly disturbances in expressive language.
(20)(52) The discrete role of the cerebellum in these
deficits has been difficult to distinguish because cerebellar injury in the term infant occurs most often in the
context of perinatal asphyxia and, specifically, the more
severe forms thereof. Of note, isolated cerebellar hemor-
cerebellar injury
rhagic injury in term infants due to coagulopathies has

been associated with a more favorable neurodevelopmental outcome. (51)
Conclusion
The consequences of injury during cerebellar development have garnered increasing research and clinical interest. This review has focused on primarily cerebrovascular insults to the developing cerebellum. Inferences
regarding vulnerability of the developing cerebellum
have been made largely in the context of the preterm
infant in whom the cerebellar insults are primarily extrauterine. Advances in fetal MRI have raised the expectation that normal cerebellar development and response of
the developing cerebellum to injury will become amenable to study during the intrauterine period. Such fetal
studies also should elucidate the role of acquired injury
during the fetal period as well as developmental cerebellar anomalies previously believed to be of primary dysgenetic (and presumably genetic) origin. An exciting area
of future research will be the ability to measure structural
and functional outcomes using MRI techniques in infants who have normal and abnormal cerebellar structure
due to early life insults. This model also provides an excellent opportunity to study transtentorial mechanisms.
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neurology
cerebellar injury
NeoReviews Quiz
1. The most striking feature of cerebellar development is its protracted time course, which extends from
approximately 4 weeks of gestation to several years after birth. This prolonged developmental program
accounts for the protracted vulnerability of the cerebellum to injury from a broad spectrum of insults. Of
the following, the structure of the developing cerebellum most vulnerable to injury is:
A.
B.
C.
D.
E.
Bergman glial cells.

External granular layer.
Inferior olivary nuclei.
Precerebellar pontine nuclei.
Purkinje cell layer.
2. A recent study of cranial ultrasonography using a mastoid approach to the posterior fossa has shown that
the incidence of cerebellar hemorrhagic injury in extremely low-birthweight (<750 g) neonates may be as
high as 19% among the survivors. Of the following, the most likely mechanism for cerebellar hemorrhagic
injury in the preterm infant is:
A.
B.
C.
D.
E.
Birth trauma.
Congenital infection.
Genetic abnormality.
Ischemia-reperfusion injury.
Peroxisomal glycosylation disorder.
3. Isolated cerebellar hemorrhagic injury, in the absence of apparent supratentorial brain lesions, has been
described in association with hypoxic-ischemic-reperfusion injury in the preterm newborn. Such injury has
long-term neurodevelopmental consequences. Of the following, the most likely neurodevelopmental
consequence associated with cerebellar hemorrhagic injury in the preterm infant is:
A.
B.
C.
D.
E.
Abnormal gait.
Global developmental delay.
Muscular hypotonia.
Oculomotor deficit.
Sensorineural hearing loss.
Cerebral White Matter Injury: The Changing Spectrum in Survivors of Preterm

Birth
Stephen A. Back and Steven P. Miller
NeoReviews 2007;8;e418-e424
DOI: 10.1542/neo.8-10-e418
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/cgi/content/full/neoreviews;8/10/e418
NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 2000. NeoReviews is owned, published, and trademarked
by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,
Illinois, 60007. Copyright 2007 by the American Academy of Pediatrics. All rights reserved.
Online ISSN: 1526-9906.
Downloaded from http://neoreviews.aappublications.org by Alaa Swaify on October 12, 2007
Article
neurology
Cerebral White Matter Injury:

The Changing Spectrum in Survivors of
Preterm Birth
Stephen A. Back, MD,
PhD,* Steven P. Miller,
Objectives
1. Describe the changing spectrum of periventricular white matter brain injury (PWMI).
2. Explain the mechanisms of PWMI.
3. Characterize the role of oligodendrocytic progenitors in PWMI.
MDCM, MAS
Author Disclosure
Supported by grants
from the National
Institutes of Health to
Dr Back (NINDS
NS41343; NS054044;
NS045737), the
American Heart
Association (Bugher
Award), and the
March of Dimes Birth
Defects Foundation.
Dr Back is a Javits
investigator of the
National Institutes of
Health. Dr Miller is
supported by the
Canadian Institutes of
Health Research and
is a Research Scholar
of the Michael Smith
Foundation.
Abstract
Despite advances in neonatal intensive care, periventricular white matter injury
(PWMI) remains the most common cause of brain injury in preterm infants and the
leading cause of chronic neurologic morbidity. Factors implicated in the pathogenesis
of PWMI during prematurity include hypoxia, ischemia, and maternal-fetal infection.
PWMI is recognized increasingly in term newborns who have congenital heart disease.
The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular
leukomalacia [PVL]) and diffuse myelination disturbances. Information about the
prevalence, severity, and distribution of white matter lesions has relied heavily on
neuropathology studies of autopsy brains. However, advances in magnetic resonance
imaging of the neonatal brain suggest that the incidence of PVL is declining; focal or
diffuse noncystic injury is emerging as the predominant lesion. Insight into the cellular
and molecular basis for these shifting patterns of injury has emerged from recent
studies with several promising experimental models. These studies support the suggestion that PWMI can be initiated by impaired cerebral blood flow related to
anatomic and physiologic immaturity of the vasculature. Ischemic cerebral white
matter is susceptible to pronounced free radical-mediated injury that particularly
targets immature stages of the oligodendrocyte lineage. The developmental predilection for PWMI to occur during prematurity appears to be related to both the timing
of appearance and regional distribution of susceptible late oligodendrocyte progenitors. It is anticipated that new strategies for prevention of brain injury in preterm
infants will develop as a result of improved recognition of changing patterns of injury
that reflect specific types of cellular vulnerability.
Clinical Features of White Matter Injury

Periventricular white matter injury (PWMI) is the major form of brain injury and the
leading cause of chronic neurologic disability in two large groups of neonates: survivors of
premature birth (1)(2)(3) and term infants who have complex congenital heart disease
(CHD). (4)(5) Despite striking improvements in the survival of very low-birthweight
(VLBW) infants (1.5 kg), there has been no reduction in the major chronic neurologic
sequelae of PWMI: the spastic motor impairments of cerebral palsy (6)(7) and a broad
spectrum of cognitive and learning disabilities. (8) Similarly, improved survival for term
neonates who have CHD has been accompanied by long-term postsurgical outcomes
dominated by a spectrum of neurologic disabilities that overlaps with that seen in preterm
survivors. (9)
Brain injury in preterm survivors and neonates who have CHD has a unique and
unexplained predilection for periventricular cerebral white matter. The major risk factors
for PWMI are prematurity, hypoxia-ischemia, and infection. (1) The period of highest risk
for PWMI is approximately between 23 and 32 weeks postconceptional age. Risk is more
*Departments of Pediatrics and Neurology, Oregon Health & Science University, Portland, Oregon
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.

neurology
Figure 1. Neuropathology of periventricular leukomalacia. A.

Gross autopsy specimens from an infant who died of complications of prematurity. Coronal views of frontal (upper specimen) and parietal (lower specimens) periventricular white
matter show multiple focal areas of severe cystic necrosis
(arrowheads). B. A coronal section of the frontal periventricular white matter (stained with hematoxylin and eosin) shows
a microscopic focus of necrosis (arrowheads) adjacent to the
lateral ventricle. The inset shows a high-power detail of the
edge of the lesion (arrows) where marked rarefaction of the
tissue can be appreciated adjacent to a region of gliosis at
lower left. Courtesy of Dr Marjorie Grafe, Oregon Health &
Science University.
heavily weighted toward infants of extremely low birthweights (500 to 1,000 g). The propensity for PWMI in
term neonates who have CHD is paradoxic; the risk
would be expected to be low based on postmenstrual
age, but recent studies support that PWMI is the major
neurologic lesion associated with CHD. (10)(11) Recent
research suggests that white matter pathology can precede surgical repair of heart lesions, (5)(12) which suggests that CHD itself may be a risk factor for PWMI.
Periventricular Leukomalacia (PVL)

PWMI has been widely appreciated since the classic
descriptions of PVL by Banker and Larroche more than
40 years ago. (13)(14)(15)(16)(17)(18) The early descriptions of PVL commonly defined lesions that were
symmetrically localized adjacent to the anterior and posterior horns of the lateral ventricles. Regions of particular
predilection for injury were the frontal and parietaloccipital periventricular white matter; the latter often
involving the optic radiations of the visual system. Figure
1 shows the typical appearance of severe PVL where
extensive cystic necrotic lesions are accompanied by enlargement of the lateral ventricles due to white matter
atrophy.
cerebral white matter injury
Figure 2. Severe white matter injuries in a newborn born at
28 weeks gestational age and scanned with MRI at 30 weeks

postmenstrual age and again at 42 weeks postmenstrual age.
The T1-weighted images demonstrate multifocal areas of T1
hyperintensity throughout the periventricular white matter of
both cerebral hemispheres that are most evident on the earlier
study. The T2-weighted images demonstrate areas of hypointensity in the subependymal region consistent with mild
germinal matrix hemorrhage. The white matter injury is most
readily apparent on the thin-section T1-weighted images.
Head ultrasonography at the time of the first MRI scan
revealed the germinal matrix hemorrhage with normalappearing white matter.
Spectrum of White Matter Injury

Whereas such devastating injury was more common a
decade or more ago, with advances in neonatal care, such
lesions now rarely are encountered. Rather, PWMI currently is recognized to include a spectrum of cerebral
injury that ranges from focal cystic necrotic lesions (PVL)
to diffuse myelination disturbances (diffuse PWMI).
(19)(20) In fact, recent neuroimaging studies support
that the incidence of PVL is markedly declining, and
focal or diffuse noncystic white-matter injury is emerging
as the predominant lesion. (21)(22)(23)(24) Focal noncystic white matter injury likely was underrecognized in
the past; ultrasonography, the traditional brain imaging
technique for diagnosing PVL, has limited sensitivity for
diagnosing focal noncystic white matter injury.
(22)(23)(25) In more recent series, cystic PVL lesions
accounted for fewer than 5% of cases. (21)((22)(23)(24)
Figure 2 shows the typical spectrum, appearance, and
distribution of lesions that often are seen by magnetic
resonance imaging (MRI). It should be emphasized that
there remains unexplained variability in the nature of
neurology
lesions detected at different centers, which may reflect

differences in clinical management or the clinical acuity
of the infants.
Advanced Magnetic Resonance Imaging

(MRI) of the Newborn Brain
The ability to recognize noncystic white matter injury
has been facilitated by the use of diffusion-weighted
imaging (DWI). (26) Using DWI, abnormal white matter signals are observed in up to 68% of former preterm
infants when studied at term equivalence. (21) Measurements of the apparent diffusion coefficient or fractional
anisotropy can detect apparent white matter injury that is
undetected by conventional MRI. (27) Thus, the sensitivity of detection of white matter lesions critically depends both on the types of modalities employed and the
timing of the study relative to the onset of injury. (28)
Advanced quantitative MRI techniques also have
been applied to detect more widespread effects of focal
PWMI. Volumetric studies have revealed decreased cerebral cortical volumes in preterm newborns who have
PVL. (29) More recently, reduced thalamic and lentiform volumes are recognized in preterm newborns, particularly among those who have white matter abnormalities. (30) More sophisticated diffusion tensor imaging
techniques can be applied to identify white matter abnormalities in the preterm newborn at term equivalent age in
the absence of focal lesions on conventional MRI. (31)
Additionally, focal noncystic white matter lesions are
associated with widespread abnormalities of white matter
development as affected preterm newborns develop to
term equivalent age. (27) Recent advances, such as probabilistic magnetic resonance tractography to measure
thalamocortical connectivity (32) and diffusion tensor
imaging to segment developmentally regulated cell layers, including the subplate zone, (33) and to measure
cortical microstructural development, (34) hold considerable promise in identifying the substrate and associated
pathologies of PWMI in vivo.
Recently, we and others have shown that the severity
of white matter injury in the preterm newborn, detected
prior to and at term-equivalent age, is associated with the
risk of adverse neurodevelopmental sequelae. (7)(35)
Although not yet the standard of care, we anticipate that
MRI and these newer MR techniques will be applied
increasingly as a means to identify those preterm survivors at high risk for developmental delay related to
PWMI.
Mechanisms of PWMI
Although the spectrum of PWMI is shifting toward
noncystic focal or diffuse brain lesions, the explanation
for these changing patterns of injury is not known. It is
possible that the decline in PVL is related to improved
clinical management of VLBW infants. One factor may
be improved surveillance for neuroinflammatory triggers, given that a correlation between maternal-fetal
infection, PWMI, and the subsequent development of
cerebral palsy has been proposed. (20)(36)(37) However, recent studies found no increased risk for cerebral
palsy in preterm survivors by examination of either intrauterine exposure to infection or inflammatory cytokines
in neonatal blood. (38)(39) Another important area of
clinical progress has been improved clinical management
of factors that contribute to cerebral hypoxia-ischemia.
These include advances in critical care to minimize blood
pressure instability and improve ventilation and oxygenation. MRI now can be used to examine how clinical care
strategies affect the risk of PWMI. (40)
In fact, a growing body of clinical and experimental
evidence suggests a role for hypoxia-ischemia in the
pathogenesis of PWMI. The propensity for the preterm
neonate to exhibit a pressure-passive circulation is related
to disturbances of cerebral autoregulation. (41)(42)(43)
Basal cerebral blood flow in healthy preterm neonates is
markedly lower than in term infants or adults.
(44)(45)(46)(47) Basal flow to cerebral white matter was
estimated to be less than 20% of that to gray matter. (48)
Impaired cerebrovascular autoregulation documented
by near-infrared spectroscopy correlated with the development of PVL and germinal matrix-intraventricular
hemorrhage. (49) However, no direct experimental evidence shows that human periventricular white matter is
selectively susceptible to ischemia. Current measures of
global cerebral blood flow lack the spatial resolution to
define cerebral hemodynamics in human periventricular
white matter. (50)
Recently, we reported in the preterm fetal sheep (0.65
gestation) the first model that reproduces the spectrum
of pathology that occurs in human PWMI. (51) The
ovine fetus is a widely studied preparation that displays
cerebral hemodynamics similar to humans and permits
repeated physiologic measurements in utero. (51)(52)
We also developed methods to quantify fetal cerebral
blood flow in utero in anatomically defined regions.
Selective periventricular white matter injury was observed in frontal and parietal periventricular white matter, two regions of predilection for human PWMI. White
matter injury of increasing severity was generated that
was proportional to the duration of cerebral ischemia.
neurology
With prolonged ischemia, selective injury to the white

matter was lost, and extensive damage to cortical and
subcortical gray matter also was observed. In fact, prolonged ischemia was associated with extensive cystic necrotic encephalomalacia, as seen in severe human PVL.
(53)(54) Hence, the neuropathologic similarities of our
model to human PWMI supports the concept that human cerebral white matter may be particularly vulnerable
to global cerebral ischemia. Moreover, the direct relation
of the severity of PWMI in preterm fetal sheep to the
duration of cerebral ischemia suggests that the current
predilection for more diffuse, noncystic forms of PWMI
in human preterm neonates may be related to the severity
of the ischemic insult.
Cellular Mechanisms of PWMI

Recent studies related to the cellular mechanisms of
PWMI suggest that cerebral ischemia does not provide a
complete explanation for the topography of white matter
injury in the developing brain. (50) Cellular maturational
factors related to susceptible oligodendrocyte progenitors (preOLs) appear to play a greater role than do
vascular factors in defining the topography of early ischemic white matter injury. The last decade has seen considerable progress in the identification of the cellular
targets that degenerate in PWMI lesions in response to
cerebral ischemia and oxidative damage. Given that the
major period of vulnerability for PWMI occurs prior to
the onset of myelination, Back and Volpe (55) first
proposed that the myelination disturbances of PWMI
might arise from targeted death of preOLs that are the
source of mature OLs. This hypothesis proposed that the
predilection for PWMI is related to a developmentally
regulated susceptibility of more immature stages of the
OL lineage to oxidative stress, a well-established sequela
of both hypoxia-ischemia (56) and maternal-fetal infection. (52) Initial support for this hypothesis came from
studies that found the developmental window of highest
risk for PWMI (ie, about 23 to 32 weeks postconceptional age) to correspond to a period in human white
matter development that preceded the onset of myelination. (57) This period coincides with the presence of one
major population of late preOLs in cerebral white matter
and identified the preOL as a potential target for injury in
PWMI. The decline in risk for PWMI coincides with the
onset of a wave of differentiation of preOLs to immature
OLs that initiate myelination of human periventricular
white matter by around 30 to 32 weeks postconceptional
age. (58) In fact, in early human PWMI lesions, significant preOL degeneration was detected in white matter
lesions that showed elevated concentrations of markers

of oxidative damage. (18)
Neurons in the subplate zone (subplate neurons) are
another developmentally regulated cell population that
play a critical role in normal visual thalamocortical development. Subplate neurons also are selectively vulnerable
to neonatal hypoxia-ischemia in a rodent model of brain
injury that is particularly relevant to injury in the human
preterm newborn. (59) In humans, similar to the preOLs, subplate neuron numbers peak at the onset of
vulnerability for white matter injury. (60)
According to studies from several experimental models, the timing of appearance and spatial distribution of
susceptible OL lineage cells is related to the magnitude
and distribution of ischemic white matter injury. For
example, we initially made the paradoxic observation that
the white matter of the 7-day-old rat was markedly more
resistant to hypoxia-ischemia than that of the 2-day-old
rat. (61) A major developmental difference at these two
ages was the preponderance of preOLs in the 2-day-old
rat, which resembles human periventricular white matter
during the high-risk period for PWMI. (62) In contrast,
at 7 days of age, the white matter in the rat is populated
primarily by a more differentiated population of OLs,
resembling near-term human tissue. PreOLs were found
to be highly susceptible to hypoxia-ischemia; earlier and
later OL stages were markedly more resistant. (61) The
enhanced susceptibility of preOLs to hypoxia-ischemia
and to oxidative stress (61)(63)(64)(65)(66)(67) is,
thus, a stage-specific property that was independent of
the postnatal age of the animal or the cerebral location of
these cells.
Consistent with these observations, we recently reported that severe global ischemia did not uniformly
damage the cerebral white matter of the preterm fetal
sheep. (51) Surprisingly, the medial and lateral frontal
periventricular white matter sustained differing degrees
of acute injury, even though they sustained a similar
degree of low flow during a prolonged severe ischemiareperfusion insult. Hence, while global ischemia was
necessary for white matter injury, no regional differences
in blood flow were found within the periventricular white
matter under any conditions to account for the disparate
rates of cellular degeneration in medial and lateral
periventricular white matter. Rather, differences in the
topography of white matter injury were related primarily
to the distribution of vulnerable preOLs. These findings
suggest that perturbations in cerebral blood flow are
necessary but not sufficient to damage cerebral white
matter. The developmental predilection for PWMI to
occur during prematurity appears to be related to both
neurology
the timing of appearance and regional distribution of

susceptible preOLs.
Emerging Questions and Future Clinical

Challenges
Although the spectrum of PWMI is shifting toward
noncystic focal or diffuse cerebral lesions, it is not known
to what extent further advances in the clinical management of preterm neonates will influence or mitigate these
changing patterns of injury. Furthermore, the application of MRI in clinical trials offers the potential of
examining directly how clinical management and emerging brain protection strategies affect the risk of PWMI.
Presumably, the pronounced reductions in the cystic
necrotic lesions of PVL will translate to better clinical
outcome. However, the long-term neurologic sequelae
of the focal or diffuse noncystic lesions may have distinctly different but still deleterious consequences for the
neurodevelopment of preterm survivors. A major challenge for our neurodevelopmental follow-up clinics will
be to evaluate systematically the motor and cognitive
development of affected children and correlate the clinical findings with the particular patterns of cerebral white
and gray matter injury defined by advanced neuroimaging.
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NeoReviews Quiz
4. Periventricular white matter injury is the most common cause of brain injury in preterm infants and the
leading cause of chronic neurologic morbidity. Of the following, the most accurate statement regarding
periventricular white matter injury in the preterm infant is that:
A.
B.
C.
D.
E.
Diffuse noncystic myelination disturbance is the predominant form of white matter injury.
Progenitors of astrocyte lineage are particularly susceptible in periventricular white matter injury.
The incidence of periventricular leukomalacia is increasing despite advances in neonatal care.
The region of particular predilection for injury is the temporal periventricular white matter.
Ultrasonography is the best imaging modality for the diagnosis of diffuse noncystic white matter injury.
5. The sensitivity of detecting white matter lesions depends largely on the modality of imaging and the timing
of the study relative to the onset of injury. Of the following, recognition of noncystic white matter lesions
is facilitated most by the technique of:
A.
B.
C.
D.
E.
Computed tomography scan.

Cranial ultrasonography.
Diffusion-weighted magnetic resonance imaging.
Magnetic resonance tractography.
Near-infrared spectroscopy.
6. Insights into the cellular and molecular mechanisms of white matter injury in the fetus and the newborn
have emerged from recent studies on topography using promising experimental models. Of the following,
the topography of white matter injury in the preterm infant is best explained by:
A.
B.
C.
D.
E.
Anatomic immaturity of specific regions of cerebral vasculature.

Distribution of oligodendrocyte progenitors.
Free radical-mediated oxidative injury.
Regional perturbations in cerebral blood flow.
Systemic maternal-fetal infection.
Cerebral White Matter Injury: The Changing Spectrum in Survivors of Preterm

Birth
Stephen A. Back and Steven P. Miller
DOI: 10.1542/neo.8-10-e418
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Article
neurology
Three-dimensional/Fourdimensional Ultrasonography to
Detect Fetal Brain Damage
Claudine Amiel-Tison,*
Julie Gosselin, Asim
Kurjak
Author Disclosure
Drs Amiel-Tison,
Gosselin, and Kurjak
did not disclose any
Objectives
1. Describe the relationship between the type of fetal brain damage and the stage of
brain maturation at the time of insult.
2. Explain why the intrauterine environment is favorable for motor activity.
3. Explain why fetal activity is more predictive for the neurologic outcome after 32 to
34 weeks gestation.
4. Describe what overlapping of sutures indicates in terms of neurologic development.
financial relationships
relevant to this
Abstract
article.
Understanding the pattern of maturation of the fetal brain sets the stage for ultrasonographic documentation of neural development or damage. General movements
and primary reflexes are the expression of spinal motor activity in the first half of
pregnancy, but increasingly complex functions denote the switch over from initial
spinal control to a higher control in the second half of the pregnancy. Both the Prechtl
Neurologic Assessment and the Amiel-Tison Neurologic Assessment at Term have
been used as the basis for proposed three- and four-dimensional ultrasonographic
criteria of central nervous system optimality and fetal central nervous system compromise. The predictive value of such imaging is limited by its hands-off observation
and the immaturity of the fetal brain, but the possibility of employing such advanced
imaging holds great promise.
Introduction
Brain damage often originates in fetal life. (1)(2) Early identification of such damage has
implications for perinatal management, and documentation of such lesions is essential in
the case of litigation. In the last 2 decades, fetal imaging with two-dimensional ultrasonography and conventional magnetic resonance imaging (MRI) has made a major contribution to the identification of classic brain lesions and malformations. The recent availability
of diffusion-weighted imaging (DWI) has allowed description of the entire spectrum of
perinatal white matter injuries in the neonate. (3)(4) The further advances of threedimensional (3D) and four-dimensional (4D) ultrasonography in exploring fetal motor
behavior should support a better clinical description of the full spectrum of fetal damage.
(5)(6)
The fetal assessment proposed in this article derives from recent data gathered by
3D/4D ultrasonography (5) interpreted in light of neurophysiology and clinical neurology in the neonate. Our objective is to select the most meaningful observations gathered
with 3D/4D ulstrasonography to identify fetal brain damage. The scope of fetal neurology
is too extensive to be described fully in the current review; discussion is restricted to the
neuromotor domain and cranial growth during the second half of pregnancy, ie, from
20 to 40 gestational weeks (GWs).
*Department of Pediatrics, Saint-Vincent de Paul Hospital, University of Paris V, Paris, France.
School of Rehabilitation, Faculty of Medicine, University of Montreal, Quebec, Canada.
Department of Obstetrics and Gynecology, Medical School, University of Zagreb, Sveti Duh General Hospital, Zagreb, Croatia.
neurology
dimensional ultrasonography
upper system is the prerequisite for

head control, sitting, walking, and
fine motor skills (Fig. 2).
Contribution of Sensory
Pathways
Recent experiments in Drosophila
embryos and larvae highlight the
importance of sensory input for the
development of motor function.
(10) The impact of induced mutation eliminating the sensory function in the Drosophilia embryonic
peripheral nervous system is expressed differently according to the
stage of development. In the embryo, the impact is primarily on the
ratio of forward/backward peristalFigure 1. Maturation of the sensorimotor network from 10 to 40 weeks gestation.
tic motor patterns, but normal
head swings still allow normal
The Developing Brain: Maturation and
hatching. Later, in the larva, the motor behaviors are very
Lesions
abnormal, with nearly exclusive backward instead of forNew insights help ultrasonography to correlate construcward movements. Moreover, head swings, which nortion of the neuronal network and emergence of the
mally disappear at this stage of development, remain
functional repertoire during fetal life.
present in the senseless larva. These findings suggest that
sensory input is essential for proper functional developSpinal Level
ment of motor circuits. Ghosh and Shatz (11) have
Initially, the central pattern generator allows swimming,
shown that sensory neurons in the human fetus are
crawling, and walking as well as rhythmic activities such
present as early as 22 GWs in the subplate. However,
as breathing and sucking. (7) Such endogenously generthalamocortical connections become functional later,
ated movements are initially independent of supraspinal
when target neurons are present in the cortical plate (Fig.
control (Fig. 1).
1).
Supraspinal Level
The review of anatomic and physiologic correlates of
early neurologic development by Sarnat (8)(9) improved
clinical understanding of the maturation of supraspinal
control and, therefore, interpretation of the evolution of
muscle tone during the second half of pregnancy. Therefore, it became possible to dissociate clinical signs associated with subcorticospinal control (lower system) and
later corticospinal control (upper system). The lower
system, consisting of the brainstem and cerebellum, matures early (beginning at 24 GWs) in an ascending wave.
Its essential role is to maintain posture against gravity and
flexor tone in limbs. The upper system, consisting of the
cerebral hemispheres and basal ganglia, matures later
(beginning at 32 GWs) and rapidly in the first 2 postnatal
years in a descending wave. Its essential role is to moderate the lower system, resulting in relaxation of the
limbs and modulation of the forces of gravity. An intact
Clinical Implications of the Sequential

Construction of the Sensory Motor System
In the first half of pregnancy, general movements (GMs)
and primary reflexes are the only expression of spinal
motor activity. By 24 GWs, descending motor pathways
as well as sensory pathways progressively modify spinal
motor activity. The timing of the hypoxic-ischemic insult
results in different clinical consequences at the different
levels previously described. Clinical observations of motor activity begin to provide information on upper structures only in the second half of pregnancy. Two different
approaches can be combined to systematize such clinical
observations. Prechtl and associates (12)(13) proposed a
clinical assessment based on the observation of GMs
from 8 GWs forward. This assessment allows observation
of the progressive organization up to 20 postnatal weeks,
demonstrating the switch over from initial spinal control
to a higher control in the course of maturation. The aim
neurology
ischemic (HI) event or a maternofetal infection occurs, the damage

can be cystic focal periventricular
leukomalacias (PVLs) as well as focal or diffuse noncystic WMI. The
first type (cystic) is easily diagnosed
by ultrasonography and conventional MRI (and, therefore, may be
identified in utero); the second
type (noncystic) can be recognized
only by DWI. Recent studies reviewed by Back (3)(4) show that:
1) both types (cystic and diffuse)
are part of a spectrum of WMI, with
noncystic injury representing a
milder degree, and 2) the incidence
of cystic PVL is declining, with diffuse noncystic WMI becoming the
predominant lesion.
Figure 2. Schematic representation of the developmental patterns of both upper and
lower motor systems. Reprinted with permission from Amiel-Tison, et al. J Perinat Med.
2006;34:437 446.
of the clinical method proposed by Amiel-Tison and

colleagues, (14)(15) which is based on the progressive
maturation of the supraspinal motor control, is to distinguish between the functions of the subcorticospinal and
the corticospinal systems (Fig. 2).
Fetal Brain Damage in Relation to

Maturational Stages
WHITE MATTER INJURY. White matter injury (WMI) is
the predominant type of brain injury in the preterm
neonate, occurring in fetal life or postnatally. WMI,
therefore, is the leading cause of cerebral palsy (CP) of
perinatal origin. The particular susceptibility of preoligodendrocytes to anoxia is consistent with abnormalities of
myelination found to various degrees in this population.
Arguments in favor of a changing spectrum of WMI are
presented by Back and Miller of this issue of NeoReviews.
(4) The fetus and the preterm neonate share similar
pathogenic mechanisms of brain damage. If a hypoxic-
GRAY MATTER ABNORMALITIES.

Neuronal damage associated with
WMI can be identified with new
imaging methods, as reviewed by
Volpe. (16) Quantitative MRI
shows reduced volume in cerebral
cortical and deep nuclear structures
as well as cerebellar lesions. This
topic is discussed in this issue of
NeoReviews by Limperopoulos and
du Plessis. (17)
SUBPLATE: A VANISHING STRUCTURE. In 1996, Volpe

(18) directed clinical attention to a huge structure developing before the cortical plate, with volume increasing
from 22 GWs to 34 GWs, then decreasing. Due to very
active apoptosis, the subplate (SP) begins to decrease in
volume by the third trimester and completely disappears
by 6 months after birth. This transient structure, therefore, shares with the germinal matrix the denotation of a
vanishing structure. Neurons of the SP originate from
the germinal matrix and subsequently migrate eccentrically, differentiating rapidly and expressing a variety of
receptors for neurotransmitters, neuropeptides, and
nerve growth factors. (11) The SP is used as a waiting
zone for axons, which later reach the thalamus and
cortical sites when their ultimate neuronal targets are
ready. Therefore, the SP is of the utmost importance for
sensorimotor organization.
What happens when SP neurons are damaged by HI?
Some of the consequences include the degeneration of
neurology
waiting neurons that are deprived of their transient target

and a lack of functional synaptic connections with the
target neurons. If thalamocortical afferent neurons fail to
reach the cortex, sensory processing is disrupted (as
noted for the experimental senseless Drosophila). The
cortical organization also is affected. Because of the
transient nature of this structure, conventional imaging
does not allow detection of such alterations in the SP.
CLINICAL IMPLICATIONS. Correlations between radiological and clinical data are both possible and important.
Two approaches support the existence of a spectrum of
abnormalities. A four-level categorization of neurologic
abnormalities at 2 years corrected age has been defined,
(19) ranging from CP (disabling or nondisabling) to
minor signs (clustered or isolated). Even though preliminary results are promising, (20) more research using
concomitant DWI and a structured clinical assessment is
needed. (21)
Early fetal damage or postnatal damage in extremely
low-birthweight (1,000 g) infants may be missed by
clinical and radiological investigations if the lesions are
located primarily in the vanishing structures (SP and
germinal matrix). Experience shows that the rate of
disabling CP in this population is not much higher than
in the population of very low-birthweight (1,000 to
1,500 g) infants, but a thorough disorganization expressed in the cognitive and behavioral functions often is
identified later. Alterations of the fetal motor function
identified by 3D/4D ultrasonography may provide the
missing link in these cases.
Technical Background
Physics and Technology of 3D/4D
Ultrasonography
By enabling synchronized spatial imaging of the entire
fetus and its movements, 4D ultrasonography offers new
prospects for quantitative assessment of fetal motor behavior. The physics and technology of 3D/4D ultrasonography have been reviewed in detail elsewhere. (22)
Recently, multicentric studies of fetal brain function have
been conducted (23)(24) with the aim of describing the
standards of fetal limb and body movements as well as
facial expressions. Such standardization is essential before establishing predictive validity in cases of prenatal
brain impairment. The Zagreb studies on fetal 4D ultrasonographic assessment, which included dynamic observations of the fetus in the first and second trimester as
well as neonatal clinical examination, also allowed dynamic 3D observations of fetal behavior. They confirmed
the feasibility of early dynamic observations in pregnancy
and showed the capacity to obtain greatly improved

images of the entire fetus. (23)(24)
Prechtl Neurologic Assessment

Prechtl has demonstrated the remarkable continuity of
endogenously generated activity from prenatal to postnatal life. The quality of his repertoire allows ultrasonographic identification of fetuses and infants who have
emerging neurologic impairment. (25) GMs include all
body movements (arms, legs, neck, and trunk) spreading
in variable sequences, with a gradual beginning and an
end. They wax and wane in intensity, force, and speed;
are fluent and elegant; and reveal the complexity and
variability of motor activity already present at this early
stage. By 36 GWs, writhing movements emerge. GMs
are analyzed on videotapes, based on visual Gestalt
perception, which provides an overall impression of
GMs with standardized procedures. (26)(27) Subsequently, movement patterns are described in terms of
complexity, variability, and fluency. GMs finally are classified as normal-optimal, normal-suboptimal, mildly abnormal, and definitely abnormal. (26) The classification
of GMs and facial expression assessed in the fetus using
3D/4D ultrasonography was derived directly from this
approach.
Amiel-Tison Neurologic Assessment at Term

By exploring passive and active tone according to neurologic maturation, (14)(15)(28) the clinician may differentiate the lower motor system and upper motor system.
Because perinatal brain damage is located in the cerebral
hemispheres in most cases, signs depending on the integrity of the upper structures, such as axial tone and alertness, as well as cranial signs linked to the volumetric
increase of the cerebral hemispheres, are emphasized.
The signs depending on brainstem function, such as
antigravity reactions and passive tone in limb flexor muscles, are de-emphasized during the neonatal period because they do not provide direct information about the
cerebral hemispheres.
Impact of Intrauterine Environment on

Motor Activity
Head Stability Passively Maintained
Grenier has demonstrated the essential role of head
instability on motor behavior during the first 2 postnatal
months. (29) In the experimental condition, manual
support is given to the neck and spine while the infants
alertness and attention are solicited by the examiner. An
amazing communication state is reached, and facial expression becomes more diversified. The most spectacular
neurology
part of the experiment follows, with jerking movements

disappearing (event termed debugging), the flexor
tone in the upper limbs decreasing, the infants hand
opening, and Moro and grasp reflexes disappearing temporarily. This particular state, termed the liberated
state, allows the infant to reach and grasp an object
intentionally. The significance attributed to this ability
transiently obtained in an infant as young as 2 weeks of
age is of high predictive importance; a positive response
brings additional confirmation of the integrity of the
upper system.
Why does demonstration of the liberated state contribute to our understanding of fetal motor behavior?
Head stability passively maintained by the uterine wall
during the second half of pregnancy obviously creates a
permanent situation comparable to the head control
transiently obtained postnatally during the previously
described experiment. Moreover, the facial expression
during the experiment in the neonate calm, concentrated, and totally involved in reaching for the object
proffered bears a very close resemblance to the facial
expression and attitude of the fetus manipulating its
umbilical cord with both hands in front of it. In addition,
the natural and permanent liberated state of the fetus
helps to explain the absence of the Moro and grasp reflex
in utero, as routinely observed. (5)(22)(23)(24)
Two speculations on these observations are tempting.
First, the fetus is very well protected, including against
itself. Although the amount of Whartons jelly can protect the umbilical vessels, it is more secure if the grasp
reflex is somewhat inhibited by the head stability in
utero. The same remark applies to the Moro reflex, which
could be a nuisance if repeatedly induced by postural
changes. Second, the young infant will have a much less
comfy life from birth until the acquisition of head
control, around 2 months postnatally. Physiologic hyperexcitability and very active primitive reflexes are wellknown transient characteristics during the first 3 postnatal months. When tested in the parents presence,
emotion peaks when the newborn begins to walk automatically, precompetence reminiscent of the evolution
since homo erectus, (30) even though this archaic performance cannot be considered useful for the newborn
or the neonatologist.
Freedom From Gravity

Long before the availability of ultrasonography, Liley
(31) commented on the differences between fetal and
postnatal motor behaviors. For example, he explained
the ability to roll over early during fetal life but not before
14 to 20 weeks of postnatal life as . . . a trick which is
simple in a state of neutral buoyancy [which] becomes

difficult under the new-found tyranny of gravity.
At the first minute of postnatal life, the most spectacular response to counteract gravity is the full righting
reaction observed when the neonate is placed in the
upright position. Tactile stimulation of the soles of the
feet provokes an active response in the extensor muscles,
and body weight is actively sustained for a few seconds.
This response depends on the brainstem (lower motor
system) and, therefore, evolves with the subcortical
structures in a caudocephalic wave (with a response restricted to the lower limbs around 28 GWs and reaching
the head by 38 to 40 GWs). (5)(12) During fetal life,
verticality is not necessary to elicit the activity of the
antigravity muscles; contact of the soles with the uterine
wall stimulates in utero the extensor muscles of the axis,
whatever the fetal position. Motility in utero is very free
indeed, under the control of brainstem reflex activity,
righting reactions, automatic walk, and trunk rotations.
However, at birth, the infant is powerless against gravity.
Later, with maturation of the upper motor system, the
infant acquires head control, independent sitting, and
independent walking in a descending maturational wave.
It is remarkable to observe how the motor system is well
prepared to protect the infant at each new victory over
the tyranny of gravity. New postural reactions occur,
such as the lateral propping reaction to maintain a sitting
position and later the parachute reaction, ready to attenuate bad falls while learning to walk. (32)
Proposals for a Structured Assessment of the

Fetus With 3D/4D Ultrasonography
The continuity in the neurologic development from preto postnatal life allows ultrasonography to derive a fetal
assessment from newborn neurologic findings.
(5)(13)(14)(15) The primary adaptations may be summarized (Table). Some criteria are identical in fetal and
neonatal assessments, such as head growth parameters,
including description of the sutures, primitive reflexes
(restricted to sucking behavior), finger movements, and
abduction of the thumb. Some of the criteria observed in
the fetus are only prerequisites for ex utero functional
achievements, such opening of the eyes for visual pursuit
and facial expressions for social interaction. Their identification by 4D imaging, in addition to efficient and
rhythmic sucking, supports the absence of central nervous system (CNS) depression. Analytic criteria of typical
passive and active tones in the neonate cannot be elicited
in the fetus, including head anteflexion tested versus
retroflexion and ventral incurvations tested versus dorsal
incurvations in the axis, both being of the utmost imporNeoReviews Vol.8 No.10 October 2007 e429
neurology
Comparison of Optimality Criteria in the Term Neonate and the

Fetus Between 20 and 40 Weeks Gestation Based on 3D/4D
Ultrasonography*
Table.
Optimality Criteria
Neonate At 40 Weeks
Gestation
Head circumference
Cranial sutures
Visual pursuit
Social interaction
Within normal limits

Same range as other growth parameters
Edge-to-edge, squamous included
Easily obtainable
Eager
Sucking reflex
Raise-to-sit and reverse
Passive axial tone
Passive tone in limbs
Opening of the eyes

Various facial expressions
Significance
Adequate hemispheric growth
Absence of central nervous

system depression
Efficient, rhythmic
Active flexion of head
Flexion > Extension
Within normal limits and
symmetric
Fingers and thumbs

movements
Autonomic control
Fetus Between 20 and

40 Weeks Gestation
Optimality should be
reflected in typical
general movements
Integrity of the upper motor

control
Independent movements of fingers

Active abduction of thumbs
No disturbance during the
assessment
Typical nonstress test
Stability of autonomic
nervous system
*Highlighted boxes indicate criteria that are similar for the fetus and the neonate.
tance postnatally to define CNS optimality. However,

optimality in the fetus should be reflected by typical
GMs.
Criteria for CNS Optimality

In terms of physiologic correlates, it is satisfactory to
cluster the different items into four subgroups according
to their conceptual meaning (Table): adequate hemispheric growth, absence of CNS depression, integrity of
the upper motor control, and stability of the autonomic
nervous system. When each item is normal, it seems
reasonable to conclude CNS optimality. A few examples
of optimality criteria have been selected to demonstrate
the precision of ultrasonographic exploration of the fetus
(Figs. 3, 4, 5).
Criteria for Fetal CNS Compromise

In addition to structural and functional impairments
observed in the course of fetal assessment, identification
of patterns of symptoms as evolving or static can help to
date the insult; the more stable the signs, the earlier the
insult. (14)(15)(28) Seizures are known to occur in
utero, with abnormally rhythmic movements occasione430 NeoReviews Vol.8 No.10 October 2007
Figure 3. Presence of membranous spaces between cranial

bones demonstrating normal head growth. Reprinted with
permission from Amiel-Tison, et al. J Perinat Med. 2006;34:
437 446.
neurology
Figure 4. Peaceful facial expression with thumb sucking that

is in favor of CNS integrity.
ally perceived and reported by mothers. However, it is

unlikely that such brief and rare events can be captured
with 4D ultrasonography. Recently, our group has produced a scoring system for the fetus that currently is
being evaluated in several centers.
Limitations of Fetal Assessment

Hands-off Observation
Haptonomists (those who use psychotactile affective
contact and interaction during prenatal life to get in
touch with the fetus) have developed the ability to play
with fetuses through the abdominal walls of the mothers,
perceiving and provoking fetal movements. Until now,
most researchers have not practiced haptonomy during
their assessment; they prioritize natural observation
without external interferences. Researchers in Zagreb
restrict their fetal assessment to the observation of spontaneous behavior and do not study responsiveness to
extrauterine stimuli. Other types of assessment, however,
take into account fetal responsiveness, such as the Fetal
Neurobehavioral Coding System derived from Brazeltons work with the neonate. (33)
The essential limitation in assessing the fetal CNS
status is the impossibility of hands-on assessment of the
fetus. For example, the most frustrating deprivation for a
pediatrician is the inability to compare passive ventral and
dorsal incurvations of the axis or evoke the activity of
flexor muscles of the neck by the raise-to-sit maneuver.
Figure 5. Full opening of the hand with abduction of the

thumb, which supports the integrity of upper motor control.
Despite these limitations, fetal assessment should prove

to be as valid as neonatal assessment for determining
both optimal status and severe degree of CNS impairment. (15)(28) Mild-to-moderate degrees of impairment also should be detectable during fetal life but
probably will not influence obstetric management at
present
Immaturity of the Fetal Brain

The primary obstacle to early prediction of CP based on
fetal observation by 3D/4D ultrasonography is the precompetent stage of most of the motor abilities observed
in utero. In other words, is it possible to predict the
presence or absence of hemispheric brain damage based
on the observation of motor and reflex activity under the
control of lower structures (brainstem and cerebellum)?
This dilemma can be illustrated by a few examples.
Automatic walking is present very early in fetal life and
at birth, subsequently diminishes in the first 3 postnatal
months, seems to disappear, but later is involved in the
automatization of independent walking for life. This is a
typical example of change of power from spinal to
supraspinal command. As a didactic joke, one can say that
fetuses and neonates walk with their feet (tactile primary
neurology
reflex), while young children and adults walk with their

heads (upper control).
Finger and thumb movements are visible very early in
fetal life (35 GWs), long before maturation of the upper
system. Fetuses start to clench and unclench their fists
from 12 GWs, and independent movements of each
finger are seen occasionally from 13 to 14 GWs. (34)
Therefore, this motor activity, initially under spinal control, later switches to upper control. An illustration is
found in children who have severe brain damage and
cannot open their hands spontaneously but do so automatically in the facial limb when eliciting the asymmetric tonic neck reflex.
Visual function is another example. (35) The data
suggest a maturational switch from birth to 2 months: A
few infants with cystic leucomalacia who later become
cortically blind seem to retain their ability to track and
show pattern preference until around 48 weeks postmenstrual age. This observation suggests that until 2 months
these functions are not dependent on cortical integrity,
but are mediated through subcortical pathways.
These few examples indicate how the clinician can
follow the switch in neural circuitry observed for each
motor acquisition according to a specific chronology.
Because most minor and moderate hypoxic-ischemic
damage is located in the cerebral hemispheres, it seems
unwise to expect reassurance about the integrity of the
upper structures based on precompetent functional
stages. Nevertheless, it remains important to test the
integrity of the lower system as a prerequisite for a
favorable outcome. This dilemma is not specific to the
neuromotor function. For example, fetal habituation,
which has attracted substantial attention as a potential
means of assessing fetal neural integrity, may be a simple
prerequisite that depends only on the lower system. (36)
Expectations
The predictive value of a complete neurobehavioral repertoire in fetuses as young as 20 GWs for a favorable
outcome is yet to be demonstrated; this is the goal of an
ongoing collaborative project by Kurjaks group using
3D/4D ultrasonography technology. Pediatricians understand the need to wait until the age of 6 months to
diagnose severe CP in infants, 12 months for moderate
CP, and 24 months for minor nondisabling CP. (19)
This delay for the full clinical expression of the functional
consequences of brain damage depends strictly on brain
maturation. Nevertheless, the possibility of employing
3D/4D ultrasonography to demonstrate the prenatal
onset of brain damage, based on morphological and
functional signs, will be of invaluable help in cases of
litigation. Any deviant observation recorded during fetal

life can serve retrospectively as a precious clue to a
prenatal insult.
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neurology
NeoReviews Quiz
7. Recent advances in brain imaging have allowed the delineation of specific types of neuronal injury in the
human fetus. Of the following, the neuronal injury that can be detected only by diffusion-weighted
magnetic resonance imaging is:
A.
B.
C.
D.
E.
Cerebellar hypoxic-ischemic lesions.

Cerebral cortical volume loss.
Cystic focal periventricular leukomalacia.
Germinal matrix hemorrhage.
Noncystic diffuse white matter injury.
8. Active abduction of the thumb is primarily under the control of:

A.
B.
C.
D.
E.
Cerebellar feedback.
Spinal motor activity.
Subcorticospinal pathway.
Corticospinal pathway.
Environmental input.
9. Stabilization of the head by manual support to the neck and spine is associated with a liberated state in
a normal newborn who has an intact corticospinal tract. Of the following, the liberated state in the
newborn observed at 2 weeks after term birth is most characterized by:
A.
B.
C.
D.
E.
Appearance of the Moro reflex.

Exaggerated jerking movements.
Increased flexor tone in the upper limbs.
Opening of the hands.
Stimulation of the plantar grasp reflex.
10. Immediately after birth, the newborn experiences for the first time many effects of gravity. The responses
to counteract the gravitational forces require an intact subcorticospinal tract. Of the following, the most
critical counter-gravity response in the newborn is reflected in:
A.
B.
C.
D.
E.
Automatic walk.
General movements.
Head control.
Righting reaction.
Trunk rotation.
Neonatal Neurologic Consultations: Integration With Maternal-fetal Medicine

and Long-term Outcome
Mark S. Scher
DOI: 10.1542/neo.8-10-e435
The online version of this article, along with updated information and services, is
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NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication,
it has been published continuously since 2000. NeoReviews is owned, published, and trademarked
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Online ISSN: 1526-9906.
Article
neurology
Neonatal Neurologic
Consultations: Integration With
Maternal-fetal Medicine and Long-term Outcome
Mark S. Scher, MD*
Author Disclosure
Dr Scher did not
disclose any financial
relationships relevant
to this article.
Objectives
1. Describe the role of maternal disease during pregnancy in terms of risk for fetal brain
injury.
2. Delineate the complication of multiple-gestation pregnancies that leads to fetal or
neonatal brain injury.
2. Explain the association of placental disease with neonatal encephalopathy and possible
injury.
3. Describe challenging presentations of intrapartum hypoxic-ischemic encephalopathy
that influence successful therapeutic intervention.
Abstract
The pediatric neurologist can serve as a subspecialty consultant for both the fetus and
neonate in whom a brain disorder is suspected. Although acute neonatal brain
disorders must be assessed and treated vigorously, neurologic disease may occur
before the intrapartum period, either from a primary brain disease or secondarily from
systemic diseases. Medical conditions during the antepartum and intrapartum periods
can predispose the fetus or neonate to express acute brain dysfunction as a neonate,
representing both acute and chronic conditions. The pediatric neurologist must,
therefore, consider maternal, placental, and fetal diseases on which a neonatal encephalopathy may be superimposed. This review describes four consultations by a neonatal
neurointensive care service in which an integrative approach to fetal neurology is
applied to neonatal consultations, emphasizing perspectives from other subspecialties
concerning maternal-fetal medicine, developmental pathology, neonatology, and
other pediatric subspecialties. Future strategies for fetal or neonatal brain resuscitation
will need to consider the developmental context in which a suspected brain injury
occurred during antepartum, intrapartum, and neonatal periods. Accurate etiologic
diagnoses and timing of an insult will influence the forms of therapy of neuroprotection or neurorescue.
Introduction
A physicians knowledge of prenatal brain development in the context of maternalplacental health and disease greatly enhances neurologic assessment of the newborn. (1)(2)
Although acute neurologic signs after birth should be investigated aggressively for peripartum or neonatal causes, brain injury also may occur during prenatal life, subsequently
modifying neonatal brain functions. Any discussion of the neurologic evaluation of the
newborn, therefore, must take into account historical and physical examination components that integrate intrauterine and extrauterine time periods, during which inherited and
acquired events may act synergistically to alter fetal brain development specific to gestational maturity. The evaluation of the neonate must take into account familial, maternal,
fetal, and placental factors to determine the developmental niche of the fetus or neonate
when stress or disease potentially alters structure and function because of time-sensitive
strengths or vulnerabilities.
*Professor of Pediatrics and Neurology, Case Western Reserve University; Division Chief, Pediatric Neurology, Director of the
Pediatric Neurointensive Care Program and the Fetal/Neonatal Neurology Program, Rainbow Babies and Childrens Hospital,
Cleveland, Ohio.
neurology
neurologic consultations
Fetal neurologic consultations commonly are requested by the maternal-fetal specialist on the basis of
developmental brain anomalies from conception or acquired brain diseases that occur during gestation. Fetal
neurologists, however, also must consider systemic disease processes of the mother, fetus, or placenta with or
without primary brain anomalies or injuries. Efforts
should be made to reach an accurate diagnosis during the
prenatal period to provide the best diagnostic and prognostic information that bridges to postnatal neurologic
consultations. The pediatric neurologist then must integrate knowledge of maternal-fetal and placental disease
processes to reach the most accurate diagnostic and
prognostic opinion for the child after birth. Given that
the postnatal diagnosis may differ from the prenatal
diagnosis in as many as one third of consultations, (3) the
neurologist is faced with ethical and moral challenges in
sharing information with the family prior to the childs
birth.
The following four maternal-fetal pair cases illustrate
how maternal-fetal-placental and neonatal diseases need
to be integrated appropriately into the neonatal neurologic consultation. These clinical presentations have been
discussed in other published formats. (2)(3)(4)(5)
Maternal Autoimmune Disorders and Fetal

Cerebrovascular Disease
Presentation
A 24-year-old primigravida female was admitted with
acute symptoms of ulcerative colitis (UC) at approximately 36 weeks gestation (1 week before delivery)
following an entire pregnancy during which she experienced no apparent symptoms of active disease. The
mothers symptoms resolved after treatment over several
days with steroids and sulfasalazine, but she subsequently
experienced uterine contractions and progressed to active labor. A cesarean section was performed 30 minutes
after signs of transient fetal distress were discerned.
A male infant was delivered who had Apgar scores at
1 and 5 minutes of 4 and 9, respectively. His birthweight
was 2,730 g, head circumference was 31.5 cm, and
length was 48.5 cm. His neurologic examination findings were normal and consistent for a postmenstrual age
of 37 weeks. At approximately 10 hours after birth, he
experienced episodes of cyanosis with feeding. A sepsis
evaluation was performed and antibiotics initiated.
Tongue darting and repetitive eye deviation were noted
subsequently, and a computed tomography (CT) scan
obtained at 21 hours after birth documented a hypodensity in the distribution of the right middle cerebral artery
(Fig. 1). Clinical seizures continued, consisting of bicye436 NeoReviews Vol.8 No.10 October 2007
Figure 1. Computed tomography scan of the brain document-
ing a stroke in the distribution of the right middle cerebral

artery.
cling of the left leg, right tonic neck deviation, and

nystagmus. Electrographic seizures were documented on
electroencephalography (EEG), and phenobarbital was
administered. Cultures were negative by 48 hours and
antibiotics discontinued. No subsequent seizures, apnea,
or cyanosis were noted. The infant was discharged on
postnatal day 7, exhibiting normal findings on neurologic examination and receiving prophylactic oral phenobarbital. Placental and umbilical cord examinations revealed no gross or microscopic pathologic findings.
The childs neurologic assessments during the first
postnatal year documented developmental delay and a
left hemiparesis. Magnetic resonance imaging (MRI) at
3 years of age confirmed a porencephaly in the right
hemisphere consistent with a cerebral infarction in the
distribution of the right middle cerebral artery. Altered
white matter signals also were noted in the centrum
semiovale of the left hemisphere, consistent with
periventricular leukomalacia. The boy presently is 15
years old and exhibits cognitive-behavioral deficits,
hemiparesis, and epilepsy that requires antiepileptic medications to control seizures.
Discussion
This case presentation illustrates the possible association
of active maternal inflammatory bowel disease (IBD)
neurology
during pregnancy with fetal brain injury resulting in

long-term neurologic sequelae. The mother became sufficiently symptomatic late during her last trimester to
require treatment. Neuroimaging after birth documented a cerebrovascular occlusion of a large intracranial
cerebral artery that correlated with neonatal seizures
without signs of accompanying neonatal encephalopathy. This clinical presentation suggests that a fetal stroke
occurred before delivery, perhaps during the time the
mother needed treatment for active IBD. In addition,
white matter gliosis in the opposite left hemisphere suggested the occurrence of additional brain injury at an
earlier fetal age (ie, 34 wk), when white matter injury
is more likely. This child suffered significant neurologic
deficits, including epilepsy, into his second decade of life.
During the prenatal period, the pediatric neurology
consultant must consider the effects of maternal autoimmune disease such as UC on the fetal brain. The distribution of cerebrovascular insults in the fetal brain is
gestational age-specific. Asphyxial or inflammatory injury
to pro-oligodendrocytes in the white matter of the preterm fetus (6) can occur, as it did to a comparatively more
subtle degree in this child. Occlusion of a large intracerebral artery more likely occurs in a fetus closer to term
age, leading to an extensive stroke within one hemisphere supplied by the middle cerebral artery. Vasoocclusive events occur in the developing white matter
more commonly in the fetal or neonatal brain at less than
34 weeks gestation, given the vulnerability of prooligodendrocytes to asphyxia and inflammation. Documentation of surrogate proteomic markers of these disease processes (ie, coagulation factors and cytokines)
have been associated with childhood neurologic disorders such as cerebral palsy and autism. (7) A partial list of
maternal, placental, and fetal diseases, including autoimmune mechanisms, should be considered by the fetal and
neonatal neurologist in determining the diagnosis and
management of brain injury (Table).
IBD affects 500,000 Americans annually. Adverse
pregnancy outcomes have been reported in several large
studies, (8) primarily involving increased risks of low
birthweight or prematurity. No studies specifically report
long-term neurologic deficits in relation to active disease
during pregnancy.
Dominitz and associates (9) documented an increased
odds risk ratio of congenital malformations in children of
mothers who had UC that may be due, in part, to
prenatal exposure to the medications to treat IBD. However, Moskovitz and colleagues (10) reported that drugs
used to treat intrauterine IBD in a cohort of 113 patients
were not associated with poor pregnancy outcomes, al-
Selected Maternal/
Placental/Fetal Factors
Considered in Fetal Neurologic
Consultations
Table.
Maternal Factors
Hypertensive disorders (ie, preeclampsia, HELLP)

Diabetes mellitus
Thyroid disease
Systemic/genitourinary infections
Blunt trauma or shock
Organ-system disorders (eg, cardiac, renal,
rheumatologic disease)
Placental/Cord Diseases
Acute infections
Acute bleeding disorders (eg, abruptio placenta, cord
rupture)
Abnormally long or short cords
Chronic placental diseases
Vascular disorders (eg, chorioangiosis, maternal
floor infarction, fetal thrombotic vasculopathy)
Anomalous villous development
Fetal Diseases
Intrauterine growth restriction

Hydrops fetalis
Multiple gestation pregnancy
Joint contractures/limb defects
Facial stigmata
Specific organ anomalies (eg, cardiac, renal, brain,
gastrointestinal anomalies)
HELLPHemolysis, elevated liver enzymes, low platelets
though no distinction between inactive and active disease

states was included.
Thromboembolic complications occur in older individuals who have IBD, including cerebrovascular occlusion. Arterial and venous thromboembolic disease is
reported in 1% to 8% of adult and adolescent patients
who have IBD, (11) with an incidence of 39% in some
postmortem studies. The risk for thromboembolic complications with IBD has been associated with a hypercoagulable state. A relationship between the severity of
inflammatory activity and prothrombotic abnormalities
has been reported. (12) Forty-eight patients who had
active UC as well as 36 individuals who had Crohn
disease were studied in more recent studies. (13)(14)
Specific thrombophilic deficits were noted, including
resistance to activated protein C and low concentrations
of free protein S compared with 61 matched healthy
neurology
controls. The authors did not discuss the neurologic

outcome of children after pregnancies in women who
experienced active disease and evidence of thrombophilia. Researchers now recommend an assessment for
thrombophilia. (15) No maternal-fetal pairs who had this
possible association have been reported previously. The
prevention of active maternal IBD during pregnancy may
be critical to optimize both maternal and fetal health.
Active IBD also causes complications related to fertility,
pregnancy health, or parturition, which negatively influences the outcome of the child.
Risk of Fetal Brain Injury During a Multiple

Gestation Pregnancy
Presentation
A 28-year-old woman who had four previous pregnancies, including two missed abortions and two living children, was pregnant with twins. She remained healthy
during the pregnancy, and a planned caesarean section
was scheduled. However, she experienced spontaneous
labor and gave birth by vaginal presentation. Pathologic
examination of the placenta demonstrated a monochorionic diamniotic placenta. Twin A exhibited Apgar scores
of 1, 4, and 6 at 1, 5, and 10 minutes, respectively and a
birthweight of 2,310 g. Twin B had Apgar scores of 8, 9,
and 9 at 1, 5 and 10 minutes, respectively and a birthweight of 2,790 g. The cord blood gas for Twin
A showed a venous pH of 7.25 with a base excess of
9 mEq/L and an arterial pH of 7.28 with a base excess
of 4 mEq/L. The venous pH for Twin B was 7.33 with
a base excess of 3 mEq/L. The total cord length for
Twin A was 21 cm compared with 27 cm for Twin B. No
growths or microscopic abnormalities were seen on placental examination.
Twin A appeared pale at birth and had a hematocrit of
15% (0.15) compared with the Twin B hematocrit of 57%
(0.57). Twin A required multiple blood transfusions and
experienced clinical seizures for which phenobarbital was
administered. Within 24 hours, Twin A developed tremors, posturing, and increased tone and experienced decreased urine output, elevated creatinine to 1.2 mg/dL
(106.1 mcmol/L), and mild increases in liver function
studies. An EEG during the first 24 hours after birth
documented a low-voltage recording with the presence
of electrographic seizures. Findings on cranial ultrasonography were normal. The child remained encephalopathic, with gradual resolution of the decreased level of
arousal and cessation of seizures. Twin B remained normal throughout the hospital course. At 3 years of age,
Twin A exhibits marked developmental delay, with microcephaly, epilepsy, and spastic quadriplegia that ree438 NeoReviews Vol.8 No.10 October 2007
quires feeding by a gastrostomy tube. Twin B is developmentally normal.
Discussion
Systemic medical conditions can predispose fetal brains
from multiple gestation pregnancies to harmful secondary effects. Multiple gestation pregnancies also can result
in the twin-to-twin transfusion syndrome that occurs in
5% to 15% of all twin pregnancies, (16) with the most
severe form occurring in 1% of monochorionic gestations. Twin-to-twin transfusion syndrome has hematologic consequences that lead to overperfusion or underperfusion to each sibling. Fetal polycythemia and anemia
are two possible complications, which predispose the
unborn child to cerebrovascular injury from hypoperfusion on the basis of either hyperviscosity or ischemia,
possibly with accompanying thrombophilia. Significant
growth discrepancy, with growth restriction in the donor
twin, may be evident on abdominal ultrasonography.
Evidence of hydrops fetalis is an ominous sign of fetal
injury. End-diastolic Doppler flow may become compromised, with loss of placental flow to one or both twins
Figure 2. Example of growth discrepancy between identical

twins. Note growth restriction in the donor twin. A sample of
Doppler flow of placental vasculature illustrates loss of enddiastolic flow, suggesting compromise of placental flow to the
donor twin.
neurology
changes consistent with fetal

thrombotic occlusive disease, including hyalinized and avascular
villi (Fig. 4).
A coagulation profile of the
child documented methyltetrahydrofolate reductase deficiency with
high homocysteine and homozygosity, with the mother as a carrier.
At 5 years of age, the child suffers
with microcephaly, spastic quadriplegia, and intractable generalized
and focal seizures that began at less
than 1 month of age. She requires
three antiepileptic medications.
Discussion
This maternal-fetal pair exemplifies
the prenatal contributions of neonatal encephalopathy with seizures
Figure 3. Tracing documenting two independently occurring electrical seizures (arrows) in children at later risk for epilepsy
on a suppressed electroencephalography background.
and developmental delay. (2) A recently published consensus report
(Fig. 2), resulting in the hydropic appearance. The intraby a multidisciplinary task force reviewed medical literauterine death of one twin results in a significantly inture concerning the association of neonatal encephalopcreased risk for cerebrovascular injuries for the surviving
athy and cerebral palsy, emphasizing antepartum as well
fetus, (17) later exhibiting cerebral palsy. Associated
as intrapartum factors that need to be considered in the
placental abnormalities also have been described in chilpathogenesis of neonatal brain disorders. (19) This child
dren who experienced brain injury manifested as motor
suffered asphyxia-induced brain insults that began durdeficits. (18)
ing the antepartum period, resulting in severe placental
thrombotic disease (20) that was caused by an inherited
Neonatal Encephalopathy With Seizures From

Chronic Placental Disease
Presentation
A 41-week female was born to a 23-year-old primigravida woman who experienced decreased fetal movements
several days before delivery. Fetal distress was diagnosed
on fetal heart rate monitoring during labor, and a neurologically depressed female infant was born at an outlying hospital, requiring transfer to a level III neonatal
intensive care unit (NICU). Intrauterine growth restriction was diagnosed based on a birthweight of 2,400 g at
39 weeks gestation. At birth, the child had an initially
reduced level of arousal, with Apgar scores of 3 at
1 minute, 6 at 5 minutes, and 8 at 10 minutes. By 7 hours
after birth, the infant manifested clinical seizures, characterized by multifocal clonic activity that was confirmed
on an EEG recording to be multifocal seizures (Fig. 3).
Neuroimaging initially included a CT scan of the brain,
followed by MRI, both of which showed diffuse cerebral
edema. The placental examination documented vascular
Figure 4. A placental sample consisting of a microscopic view
with magnification 100, H/E stain of placental villi showing

hyalinized avascular villi (arrows) intermixed with normal villi
on the maternal side of the placenta.
neurology
thrombophilia (ie, methyltetrahydrofolate reductase deficiency). Vascular occlusive disease on the maternal side
of the placenta led to severe hypoperfusion-induced asphyxial brain injuries to the newborn brain, which began
in the antepartum period and continued during parturition.
Clinicians should consider a continuum of injury for
some neonates presenting with encephalopathy beginning antepartum and extending into the intrapartum
period. This concept of dual pathology initially was defined for populations of children and adults who had
intractable seizures requiring evaluation for epilepsy surgery. Dual pathology implies the existence of more than
one cerebral lesion in addition to temporal lobe abnormalities, principally medial temporal sclerosis. Historically, the concept of dual pathology referred to febrile
status epilepticus during infancy in humans in association
with cortical dysplasias that were acquired during gestation.
Cumulative risks for brain injury throughout the three
trimesters of pregnancy, including parturition and the
neonatal period, may include both malformations from
genetic defects and lesions from acquired injuries. Dual
pathology in the fetus and the neonate underscores the
importance of recognizing that multiple brain lesions
may occur at different time periods and cumulatively add
to the negative effects of developmental neural plasticity,
which contribute initially to neonatal encephalopathy as
well as subsequent epileptogenesis and developmental
delay. (21)(22) Metabolic pathways for neurogenesis
and epileptogenesis are shared; microdysgenesis (23)
found in surgical pathologic specimens at the time of
epilepsy surgery in adults and children are prenatal in
origin from both genetic and acquired causes. Different
patterns of heterotopic neurons and abnormal cortical
architecture may occur early or late during the first or
second half of pregnancy from different disease states as
well as from genetic defects. Epigenetic effects also may
result when the fetus is exposed to harmful environmental conditions while in utero. This may involve toxic,
infectious, or metabolic (including asphyxial) stresses
that alter genetic expression. For example, hippocampal
sclerosis was uncommon in children who had fetal
strokes before 28 weeks gestation compared with children whose strokes occurred later in gestation. (24) This
type of analysis provides evidence that the timing of
prenatal insults has profound influences on subsequent
brain pathology and clinical outcome. Neonatal encephalopathy with seizures, as occurred in this clinical presentation, underscores the importance of dual pathology as
it relates to fetal brain injury acquired both before and
during parturition and expressed after birth by encephalopathic signs. (25) Consideration of time, region, and
etiologic-specific contributions to dual pathology may
alter the definition of intractable epilepsy later during
childhood. Such findings should lead to reconsideration
of novel pharmacologic interventions and more aggressive surgical intervention when deemed appropriate.
Historical data, clinical findings, and laboratory information must be placed along a timeline that considers
prenatal time periods during which brain malformations
or damage occur in the context of the childs genetic
endowment. The pediatric neurologist who appreciates
fully the childs risk for epilepsy and comorbidities involving cognition and behavior applies an ontogenetic
approach to the neurologic evaluation beginning before
birth to consider the epileptic condition from a fetal
neurologic perspective. This fetal perspective consequently influences the type and timing of medical or
surgical interventions, even as early as the neonatal period.
Intrapartum Hypoxic-ischemic
Encephalopathy
Presentation
A Caucasian female was born at 38 weeks gestation to a
gravida 2 para 12 female whose pregnancy was complicated by a flulike illness in the first trimester and mild
pregnancy-induced hypertension that was treated with
only bed rest. The mother was admitted to an outlying
hospital with the spontaneous onset of labor after artificial rupture of membranes at 19 hours prior to delivery.
Meconium-stained amnionic fluid was noted. A prolonged second stage of labor of more than 4 hours
followed. The child was delivered by vaginal presentation
without instrumentation and required resuscitation with
positive-pressure ventilation after transient intubation
for suctioning. No meconium was noted below the vocal
cords. Apgar scores were 2, 5, and 7 at 1, 5, and 10 minutes, respectively, and the cord pH was 7.07. The child
initially had cyanosis, hypotonia, and decreased peripheral perfusion. She improved rapidly and did not require
ventilatory assistance or supplemental oxygenation after
the initial resuscitative effort. At 10 minutes after birth,
findings on her clinical examination were assessed to be
age-appropriate, and she was transferred to a well child
nursery. Her birthweight was 2,820 g.
At 6 hours of age, the child appeared somewhat slow
to feed by bottle, but no significant clinical abnormalities
were noted during the first 12 hours after birth. At
approximately 12 hours of age, the child developed
periods of slow breathing and clinical seizurelike activi-
neurology
deemed normal. On day 5, MRI

diffusion-weighted imaging (DWI)
documented diminished diffusion
indicative of ischemic injury in the
frontal and parietal lobes. Initial laboratory findings included a sodium
of 125 mEq/L (125 mmol/L), potassium of 4.1 mEq/L (4.1 mmol/
L), chloride of 82 mEq/L
(82 mmol/L), anion gap of
30 mEq/L (30 mmol/L), blood
urea nitrogen of 22 mg/dL
(7.9 mmol/L), creatinine of
0.9 mg/dL (68.6 mcmol/L), calcium of 6.8 mEq/L (6.8 mmol/L),
and albumin of 3.1 g/dL (31 g/L).
A white blood cell count was
15.7103/mcL
(15.7109/L),
hemoglobin was 15 g/dL (150 g/
L), hematocrit was 42.1% (0.421),
Figure 5. Chronic placental lesion demonstrating hemosiderin-laden macrophages and and platelet count was 196103/
focally avascular villi.
mcL (196109/L); no nucleated
red blood cells were noted. Cereties and accompanying hypoxemia with PO2 readings to
brospinal fluid studies revealed no pleocytosis, with northe 50s. Subtle migratory clonic activity of the left foot
mal protein, lactate, and pyruvate concentrations.
and hand and right toe were noted, along with lateral eye
During the first 48 hours after transfer, the childs
deviation to the left or right. Each episode lasted for
renal output remained normal, and her liver function
approximately 3 to 5 minutes. When a third clinical
studies remained within normal limits. A metabolic
seizure event occurred, the child was intubated and
screen for inherited genetic diseases had normal results.
phenobarbital infused at 40 mg/kg. The clinical moveShe weaned off the ventilator rapidly and was extubated
ments persisted, and she was transferred to a level III
within 1 day after birth, tolerating room air by 4 days of
NICU.
age. She was feeding adequately by 6 days of age at the
On arrival at the NICU, the child satisfied clinical
time of discharge.
criteria for 38 weeks gestational age, with a birthweight
The placenta showed changes indicative of chronically
of 2,820 g (40th percentile), length of 48 cm (50th
decreased maternal perfusion, including a placental
percentile), and head circumference of 34 cm (60th
weight less than the 10th percentile for a 38-week gestapercentile). No dysmorphia was noted. Frequent clinical
tion and increased syncytial knots with microinfarcts.
seizures were noted at the time of admission, and a
Chronic peripheral separation with 100% circumvallasynchronized video EEG monitoring documented status
tion, an old marginal blood clot, hemosiderin-laden
epilepticus consisting of eight electrographic/clinical
macrophages and focal green (biliverdin) discoloration
events over a 40-minute recording. Clinical seizures coof the placental membranes, and focal avascular villi
incident with the EEG seizures consisted of buccolingual
indicative of upstream fetal vascular occlusion were
movements, staring, right hand tonic and clonic movenoted (Fig. 5). In addition, the placenta showed two
ments, and bicycling. Ictal movements persisted despite
subacute lesions of at least 12 to 24 hours duration.
additional phenobarbital boluses as well as phenytoin
Finally, acute chorioamnionitis with intense chorionic
and diazepam infusions. Urine, blood, and cerebrospinal
vasculitis and an increase in circulating fetal nucleated red
fluid examinations failed to document infection, hemorblood cells was apparent (Fig. 6).
rhage, or metabolic disease. Systemic hypothermia was
The child was examined at 3, 6, and 10 months of age.
not yet available. Cranial ultrasonography and CT scan
By 3 months of age, she demonstrated microcephaly
on the day of admission were read as normal. T1- and
T2-weighted MRI was obtained on day 3 and also was
(occipitofrontal circumference 3rd percentile). At 5
neurology
tion after a transient episode of asphyxia at birth, documented by the

need for resuscitation and a cord pH
of 7.07. Other than minimal difficulty with feeding at 6 hours of age,
no other clinical signs of suspected
neurologic dysfunction were noted
until 12 hours of age, when status
epilepticus began abruptly. Given
the apparent symptom-free interval
since resuscitation, other etiologic
possibilities needed to be considered rapidly, including intracranial
hemorrhage, occlusive vascular disease, infection, and metabolic disease. Whether earlier EEG monitoring during the asymptomatic period
would have documented significant
encephalopathic changes remains
speculative. Aggressive use of EEG
Figure 6. Microscopic specimens of a placenta documenting acute chorioamnionitis with
to assess for neonatal brain disorintense chorionic vasculitis and increased circulatory fetal nucleated red blood cells.
ders, specifically seizures, has been
emphasized. (2)(25)
The second caveat of this case was the abnormal
years of age, she is markedly delayed in all domains of
neuroimaging findings. Only the DWI MRI images apdevelopment and has intractable seizures.
peared abnormal. The initial CT scan followed by conventional T1- and T2-weighted MRI images failed to
Discussion
document any radiographic abnormalities, including ceAnimal models of asphyxia-induced brain damage differrebral edema. Whether this patient would have had an
entiate between early cell death immediately following
abnormal DWI MRI finding closer to the time of birth is
asphyxia and a reperfusion phase of injury within 6 to
uncertain. Although adult patients demonstrate changes
12 hours, reflecting mitochondrial dysfunction, energy
on DWI studies within hours after an ischemic injury, the
failure, and additional neuronal and glial death or injury.
evolution of hypoxic-ischemic injury in the neonatal
(26) This biphasic description for the pathogenetic
brain on DWI is less clear. DWI increases visualization of
mechanisms of asphyxia-induced brain injury may exthe number and extent of ischemic foci compared with
plain the wide range of clinical presentations of children
conventional MRI, (29) but still is believed to underesafter significant acute insult. The traditional clinical stagtimate hypoxic-ischemic injury during the first 48 to
ing after hypoxia-ischemia was described more than 30
72 hours after asphyxia in the neonate. (30) Studies using
years ago and suggested mild, moderate, or severe preneonatal rats have documented a variation in signal on
sentations of clinical and neurophysiologic changes,
DWI that initially is abnormal, followed by a transient
which optimally are assessed by 24 hours of age. (27)
return to normal within several hours and a subsequent
Variations from the expected clinical presentation over
reversal to abnormal signal within 24 to 72 hours, supthe initial 6 to 12 hours after a presumed acute asphyxial
porting the idea of biphasic or delayed energy failure.
stress also may occur before the subsequent reperfusion
(31)(32) More recently, Barkovich and associates (33)
phase of brain injury. This is a challenge to the neonatolhave found that MR spectroscopy (MRS) is more sensiogist who has limited time to evaluate the infant sustive to the presence of hypoxic-ischemic injury, even
pected of acute intrapartum asphyxia and introduce neuduring this early period of false-negativity on DWI, sugroprotective interventions for neuroresuscitation such as
gesting that MRS may become an important adjunct in
hypothermia. (28)
imaging the asphyxiated neonate. Although not available
This maternal-fetal pair highlights three challenging
for this child, systemic or head cooling to induce modpoints for the neonatologist and neurologist. First, the
erate hypothermia would be less effective beyond 6 to
neonate had minimal or no significant clinical dysfunce442 NeoReviews Vol.8 No.10 October 2007
neurology
8 hours when the reperfusion phase of postasphyxial

injury occurs.
Third, although this child probably suffered an intrapartum asphyxial brain injury, it is interesting to note that
chronic placental disease resulting in decreased maternal
and fetal perfusion contributed to the acute asphyxial
stress during the prolonged second stage of labor. Antepartum placental disease, however, significantly compromised placental blood flow, which could not sustain
blood flow to the fetus during parturition. In the absence
of such chronic pathologic lesions of the placenta, it may
have been less likely that the child would have suffered
such a severe degree of neurologic injury. Recent work
has highlighted the importance of multiple synergistic
placental processes with different times of onset as being
particularly relevant for decreased placental reserve. (34)
The specific lesions in this case chronic peripheral separation (chronic abruption), avascular villi, intense
chorionic vasculitis, and increased nucleated red blood
cells have been implicated in adverse neurologic outcome. Careful pathologic evaluation of the placenta is
required in the evaluation of the neonate who has asphyxia.
This particular form of clinical presentation after asphyxia suggests that at least a subset of patients may not
be identified easily for aggressive neuroresuscitative measures using moderate hypothermia during the crucial
hours after a recently acquired severe asphyxial injury.
The onset of intractable neonatal seizures that are unresponsive to antiepileptic medications may reflect the
reperfusion phase of asphyxial brain injury at a time
beyond which therapeutic benefits of specific neuroresuscitation options such as hypothermia are less effective.
Aggressive use of newer MRI modalities, EEG, and
placental examinations may better diagnose and follow
the clinical time course of injury after asphyxial stress to
guide specific strategies for neuroprotection as a function
of timing. (35)
Conclusion
The pediatric neurologist can play an important consultative role in the NICU, bridging information learned
during fetal life into the neonatal period and integrating
medical care for the child in the context of the maternal,
placental, and fetal factors. Although the conventional
role of the pediatric neurologist has been to evaluate the
child only after birth, knowledge of maternal-fetalplacental disease by the fetal neurologic consultant can
help to anticipate the condition of the child evaluated
after birth as well as at older ages for neurologic deficits.
The neonatal neurologists assessment of levels of
arousal, altered muscle tone, presence of seizures, and

effects of systemic diseases on the central nervous system
must be integrated with a traditional knowledge base of
developmental neurology and interdisciplinary medical
issues that span antepartum, peripartum, and neonatal
time periods.
References
1. Scher MS. Fetal and neonatal neurologic consultations: identifying brain disorders in the context of fetal-maternal-placental
disease. Semin Pediatr Neurol. 2001;8:5573
2. Scher MS. Fetal neurologic consultations. Pediatr Neurol. 2003;
29:193202
3. Scher MS, Kidder BM, Shah D, Bangert BA, Judge NE. Pediatric neurology participation in a fetal diagnostic service. Pediatr
Neurol. 2004;30:338 344
4. Scher MS, Kidder BM, Bangert BA, Redline RW, Cohen ML.
Pediatric epilepsy evaluations from the prenatal perspective. J Child
Neurol. 2007;22:396 401
5. Scher MS, Redline RW, Bangert BA. Delayed onset of status
epilepticus after transient asphyxia in an asymptomatic full-term
neonate. J Child Neurol. 2002;17:780 83
6. Kinney HC. Human myelination and perinatal white matter
disorders. J Neurol Sci. 2005;228:190 192
7. Nelson KB, Dambrosia JM, Grether JK, et al. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann
Neurol. 1998;44:665 675
8. Norgard B, Fonager K, Sorensen HT, Olsen J. Birth outcomes
of women with ulcerative colitis: a nationwide Danish cohort study.
Am J Gastroenterol. 2000;95:31653170
9. Dominitz JA, Young JC, Boyko EJ. Outcomes of infants born to
mothers with inflammatory bowel disease: a population-based cohort study. Am J Gastroenterol. 2002;97:641 648
10. Moskovitz DN, Bodian C, Chapman ML, et al. The effect on
the fetus of medications used to treat pregnant inflammatory boweldisease patients. Am J Gastroenterol. 2004;99:656 661
11. Talbot RW, Heppell J, Dozois RR, Beart RW Jr. Vascular
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12. Koutroubakis IE, Sfiridaki A, Mouzas IA, et al. Resistance to
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with inflammatory bowel disease. Am J Gastroenterol. 2000;95:
190 194
13. Ferrero S, Ragni N. Inflammatory bowel disease: management
issues during pregnancy. Arch Gynecol Obstet. 2004;270:79 85
14. Lamah M, Scott HJ. Inflammatory bowel disease and pregnancy. Int J Colorectal Dis. 2002;17:216 222
15. Spina L, Saibeni S, Battaglioli T, et al. Thrombosis in inflammatory bowel diseases: role of inherited thrombophilia. Am J
Gastroenterol. 2005;100:2036 2041
16. McCulloch K. Neonatal problems in twins. Clin Perinatol.
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17. Larroche JC, Droulle P, Delezoide AL, et al. Brain damage in
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18. Benirschke K. The contribution of placental anastomoses to
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26:80 85
21. Parent JM. The role of seizure-induced neurogenesis in epileptogenesis and brain repair. Epilepsy Res. 2002;50:179 189
22. Swann JW. The effects of seizures on the connectivity and
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23. Eriksson SH, Malmgren K, Nordborg C. Microdysgenesis in
epilepsy. Acta Neurol Scand. 2005;111:279 290
24. Squier M, Keeling JW. The incidence of prenatal brain injury.
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25. Scher MS. Neonatal seizure classification: a fetal perspective concerning childhood epilepsy. Epilepsy Res. 2006;70(suppl 1):S41S57
26. Fellman V, Raivio KO. Reperfusion injury as the mechanism of
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27. Sarnat HB, Sarnat MS. Neonatal encephalopathy following
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29. Johnson AJ, Lee BCP, Lin Weili. Echoplanar diffusionweighted imaging in neonates and infants with suspected hypoxicischemic injury. AJR Am J Roentgenol. 1999;172:219 226
30. Robertson RL, Ben-Sira L, Barnes PD, et al. MR line-scan
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31. Tuor UI, Kozlowski P, Del Bigio MR, et al. Diffusion and
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after acute cerebral hypoxia-ischemia in the neonatal rat: a combined
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34. Redline RW, ORiordan MA. Placental lesions associated with
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35. Scher MS. Neonatal seizures and brain damage. Pediatr Neurol. 2003;29:381390
NeoReviews Quiz
11. Maternal autoimmune disease, such as ulcerative colitis, is associated with gestational age-specific insults
to the fetal brain. Of the following, the fetal brain insult caused by occlusion of a large cerebral artery in
association with maternal autoimmune disease is most likely to occur at a gestational age of:
A.
B.
C.
D.
E.
12
18
24
30
36
to
to
to
to
to
17
23
29
35
41
weeks.
weeks.
weeks.
weeks.
weeks.
12. Twin-twin transfusion syndrome occurs in 5% to 15% of all twin pregnancies, with the most severe form
occurring in 1% of monochorionic gestations. Of the following, the risk for brain injury in the donor twin
in a twin-twin transfusion syndrome most likely results from:
A.
B.
C.
D.
E.
Antepartum asphyxia.
Intrapartum asphyxia.
Placental abnormality.
Polycythemia-hyperviscosity.
Thrombophilia.
13. Hypoxic-ischemic encephalopathy following an acute asphyxial insult has a wide range of clinical
presentations in the newborn. The need to implement neuroprotective interventions, such as hypothermia,
within a few hours after birth makes it critical to identify infants, particularly those who have clinically
silent manifestations, with appropriate neuroimaging techniques. Of the following, the most promising
neuroimaging technique for the identification of an asymptomatic asphyxiated neonate is:
A.
B.
C.
D.
E.
Computed tomography scan.

Cranial ultrasonography.
Diffusion-weighted magnetic resonance imaging.
Magnetic resonance spectroscopy.
Near-infrared imaging.
Neonatal Neurologic Consultations: Integration With Maternal-fetal Medicine

and Long-term Outcome
Mark S. Scher
DOI: 10.1542/neo.8-10-e435
Updated Information
& Services
including high-resolution figures, can be found at:

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s;8/10/e435
Permissions & Licensing
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tables) or in its entirety can be found online at:
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index of suspicion in the nursery
Case
The reader is encouraged to write

possible diagnoses for each case
before turning to the discussion.
We invite readers to contribute
case presentations and discussions.
Please inquire first by contacting
Dr. Philip at aphilip@stanford.edu.
Author Disclosure
Drs Vachharajani, Kuhlman, and
Hackett did not disclose any
Presentation
A female infant is born by cesarean

section at 35 weeks estimated gestational age to a primigravida woman
after a pregnancy complicated by hypertension, gestational diabetes mellitus, and bipolar disorder with a history of suicide attempts. The mother
has been off medications for an undetermined amount of time. Her
blood type is A, and results of serologic tests, including group B Streptococcus status, are unremarkable.
Delivery was complicated by spontaneous rupture of membranes at
12 hours prior to delivery and variable decelerations. The mother received butorphanol tartrate for pain
control. Apgar scores are 8 and 9 at
1 and 5 minutes, respectively.
The infants birthweight is
2,995 g (50th percentile), length is
48.5 cm (55th percentile), and head
circumference is 33.5 cm (55th per-
centile). The remainder of the physical examination findings are unremarkable. A few hours after birth, the
infant begins to have episodes of apnea and bradycardia. Naloxone administration results in no change,
and antibiotic therapy is initiated.
Results of a complete blood count,
chest radiography, and cerebrospinal
fluid examination are normal. Blood,
cerebrospinal fluid, and urine cultures are negative. Electroencephalography and electrocardiography
results are normal. A computed tomography scan of the head reveals
small subarachnoid hemorrhages in
the left middle cranial fossa. The infant is intubated and placed on mechanical ventilation with low settings
when the apnea does not respond to
continuous positive airway pressure
and aminophylline. When the clinicians see the babys father 24 hours
later and obtain a brief family history,
they determine the diagnosis.
financial relationships relevant to

this case.
Case Discussion
The initial differential diagnosis in
this infant included respiratory suppression due to maternal butorphanol tartrate administration or surreptitious maternal opiate use, infection,
apnea of prematurity, seizure, or intracranial hemorrhage. When the father arrived to visit his newborn
daughter, clinicians observed that he
had a tracheostomy and a diaphragmatic pacer attached to his belt. When
questioned about these, the father replied, I have CCHS. Do you think
my daughter might have it too?
The Condition
Congenital central hypoventilation
syndrome (CCHS) (also termed Ondines curse), is a rare disorder of
respiratory control with an estimated
incidence of 1 in 200,000 live births.
The disorder generally is characterized by a normal respiratory pattern
in the awake state and hypoventilation with hypercapnia and hypoxemia during sleep. In more severe
cases, the respiratory pattern also is
affected while awake. Minute ventilation is decreased by both a decrease
in tidal volume and a decrease in
respiratory rate. There is a negligible
or absent respiratory response to hypercapnia or hypoxemia. In general,
neuroimaging does not reveal any
central nervous system abnormalities. In particular, the brainstem appears to be anatomically normal.
There is no other evidence of neuromuscular, pulmonary, or cardiac disease.
Respiratory control involves input
from peripheral and central chemoreceptors for hypercapnia and hypoxia to brainstem nuclei that include
the pre-Botzinger complex. This input regulates the activity of an intrinsic oscillator that controls the respiratory pattern. In patients who have
CCHS, the response to both types of
chemoreceptors is blunted or absent.
While awake, cortical input can overcome the blunted response. Affected
patients can increase their minute
ventilation with exercise but not to
the same extent as unaffected people,
and older patients may develop feelings of dyspnea with exercise. Although the brain is structurally normal in CCHS, functional magnetic
resonance imaging reveals abnormalities, including abnormal neural responses to hypercapnia and hypoxia,
based on changes in blood oxygendependent signals, in a variety of central nervous system nuclei.
The Diagnosis
CCHS can be diagnosed in a newborn who has hypoventilation in the
absence of primary neuromuscular,
pulmonary, cardiac, or metabolic disease. Additionally, acquired causes of
respiratory control dysfunction, such
as hypoxic-ischemic encephalopathy,
infection, and central nervous system
hemorrhage or infarction, should be
excluded. In this case, making the
diagnosis was simplified significantly
by the convincing family history.
Many cases, however, are sporadic
and may require more extensive evaluation to eliminate other possible
causes. A sleep study may be helpful
in confirming the diagnosis. Genetic
testing also is available.
CCHS has been associated with
other disorders that involve defective migration or differentiation of
neural crest cells. The most common
associated disorder is Hirschsprung
disease, which occurs in up to 20%
of patients who have CCHS. Tumors
of neural crest cell origin, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, also
have been described in those who
have CCHS. Such findings suggest
that the origin of CCHS may involve neural crest cell abnormalities,
but no direct evidence yet supports
this hypothesis. Patients who have
CCHS have other evidence of autonomic system dysfunction, including

heart beat variability and dysrhythmia, gastrointestinal motility, abnormal pupillary responses, and disorders of sweating and temperature
regulation. Thus, although hypoventilation may be the most readily apparent feature of CCHS, autonomic
dysfunction may be more widespread
than generally appreciated.
Genetics
Most cases of CCHS are sporadic,
although familial cases have been described. There also are reports of
increased autonomic dysfunction in
the parents of affected patients.
CCHS is inherited in an autosomal
dominant pattern. The most commonly mutated gene is the PHOX2B
gene, accounting for more than
90% of the identified mutations.
PHOX2B is a member of the pairedlike homeobox gene family and is
characterized by two polyalanine repeat regions. The most common
mechanism for mutation involves expansion of the polyalanine repeat in
exon 3. The expansion is inherited in
a stable fashion. Frameshift, nonsense, and missense mutations also
have been described. Genotype and
phenotype appear to correlate, with
the most severe disease associated
with a greater increase in the number
of polyalanine repeats. The severity
of respiratory symptoms and the risk
of Hirschsprung disease and neural
crest tumors are greater in the nonpolyalanine repeat mutations. Mice
heterozygous for a targeted mutation in the PHOX2B gene demonstrate a blunted response to hypoxia
and hypercapnia compared with
wild-type mice and abnormal development of chemoreceptors. Although significantly less common,
mutations in the RET, GDNF,
EDN3, BDNF, and ASCL1 genes
also have been identified in patients

who have CCHS.
Management
Management is targeted to prevent
hypercapnia and hypoxemia. Some
form of mechanical ventilation is required because supplemental oxygen
alone is not adequate to prevent hypoventilation with hypercapnia and
the subsequent development of pulmonary hypertension. A variety of
mechanical ventilation strategies
have been used, including positivepressure ventilation through a tracheostomy and bilevel positivepressure ventilation through a face
mask. Diaphragm pacing via electronic stimulation is another option
and affords greater portability, allowing for at least some periods of time
free from mechanical ventilation. Respiratory stimulants, such as caffeine,
have no role in the management of
CCHS.
Outcome
CCHS is a lifelong disorder that requires lifelong respiratory support.
With attention to care, most affected
patients survive into adulthood. Neurodevelopmental outcomes of affected
children vary widely, but the average

child has some degree of neurodevelopmental delay. This may be the result
of intermittent episodes of hypoxia,
but a primary effect of the mutation on
cognitive ability cannot be excluded.
A gastrostomy to insure adequate nutrition also is not uncommon, particularly in the newborn period.
Lesson for the Clinician

Common causes of apnea include
prematurity, infection, intracranial
hemorrhage, and metabolic disorders. Eliciting a family history remains a useful and time-tested modality of clinical investigation, as
illustrated by this case. (Akshaya
Vachharajani, MD, Department of
Pediatrics, Washington University
School of Medicine, St. Louis, Mo.;
Sarah Kuhlman, MD, CoxHealth,
Springfield, Mo.; Brian Hackett, MD,
Department of Pediatrics, Washington University School of Medicine, St.
Louis, Mo.)
Suggested Reading
Berry-Kravis EM, Zhou L, Rand CM,
Weese-Meyer DE. Congenital central
hypoventilation syndrome. PHOX2B
mutations and phenotype. Am J Respir

Crit Care Med. 2006;174:1139 1144
Dauger S, Pattyn A, Lofaso F, et al.
PHOX2B controls the development of
peripheral chemoreceptors and afferent
visceral pathways. Development. 2003;
130:6635 6642
Harper RM, Macey PM, Woo MA, et al.
Hypercapnic exposure in congenital
central hypoventilation syndrome reveals CNS respiratory control mechanisms. J Neurophysiol. 2005;93:1647
1658
Macey PM, Woo MA, Macey KE, et al.
Hypoxia reveals posterior thalamic,
cerebellar, midbrain, and limbic defects in congenital central hypoventilation syndrome. J Appl Physiol. 2005;
98:958 969
OBrien LM, Holbrook CR, Vanderlaan
M, Amiel J, Gozal D. Autonomic
function in children with congenital
central hypoventilation syndrome and
their families. Chest. 2005;128:2478
2484
Trang H, Dehan M, Beaufils F, Zaccaria I,
Amiel J, Gaultier C. French CCHS
Working Group. The French congenital
central hypoventilation syndrome registry: general data, phenotype, and genotype. Chest. 2005;127:7279
Weese-Mayer DE, Berry-Kravis EM. Genetics of congenital central hypoventilation
syndrome. Lessons from a seemingly orphan disease. Am J Respir Crit Care
Med. 2004;170:16 21

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educational perspectives

Portfolios: The Next

to a portfolio. A portfolio may be

ciency of the teaching standards

proved feedback. In 2001, the Department of Surgery at the Medical

Patient and Procedure Logs

Neonatal Resuscitation Program

Inservice board examination

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have suggested that use of strategies

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the program director both with improved assessment of the resident

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e408 NeoReviews Vol.8 No.10 October 2007

%20Project%20Research.pdf. Accessed July

12. Jarvis RM, OSullivan PS, McClain T,

Injury to the Developing

After completing this article, readers should be able to:

and du Plessis did not

Normal Development of the Cerebellum

Injury to the Developing Cerebellum

Injury to the Preterm Cerebellum

prevalence of CHI has been underestimated in these

lesions often occur together and

Injury to the Term

Cerebellar hemorrhage in the term

Figure 2. Axial view T2-weighted fast spin-echo (3555/

112) image obtained through the posterior fossa in a

showed loss of Purkinje and eosinophilic Purkinje cells

Structural Consequences of Injury to the

Figure 3. Coronal view T2-weighted fast spin-echo (6480/

study of growth and development in remote cerebral

Cerebellar Growth Failure Following CHI in

pratentorial lesions occurred commonly, but injury was confined to

CEREBELLAR DEVELOPMENT IN PRETERM INFANTS

Functional Consequences of Injury to the

adults, children who have cerebellar lesions, such as

Functional Outcome of Preterm Cerebellar

recent case-controlled study, in which 35 infants who

Functional Outcome of Term Cerebellar Injury

rhagic injury in term infants due to coagulopathies has

32. Limperopoulos C, Soul JS, Gauvreau K, et al. Late gestation

Bergman glial cells.

NeoReviews Vol.8 No.10 October 2007 e417

Cerebral White Matter Injury: The Changing Spectrum in Survivors of Preterm

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Cerebral White Matter Injury:

After completing this article, readers should be able to:

Clinical Features of White Matter Injury

Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.

Downloaded from http://neoreviews.aappublications.org by Alaa Swaify on October 12, 2007

Figure 1. Neuropathology of periventricular leukomalacia. A.

Periventricular Leukomalacia (PVL)

cerebral white matter injury

Figure 2. Severe white matter injuries in a newborn born at

28 weeks gestational age and scanned with MRI at 30 weeks

Spectrum of White Matter Injury

Downloaded from http://neoreviews.aappublications.org by Alaa Swaify on October 12, 2007

cerebral white matter injury