The Near-Term (Late Preterm) Human Brain
and Risk for Periventricular Leukomalacia: A Review
Hannah C. Kinney, MD
Historically the major focus in neonatal neurology has been on brain injury in premature
infants born less than 30 gestational weeks. This focus reflects the urgent need to improve
the widely recognized poor neurological outcomes that occur in these infants. The most
common underlying substrate of cerebral palsy in these premature infants is periventricular
leukomalacia (PVL). Nevertheless, PVL also occurs in near-term (late preterm), as well as
term, infants, as documented by neuroimaging and autopsy studies. In both very preterm
and late preterm infants, gray matter injury is associated with PVL. In this review, we
discuss the cellular pathology of PVL and the developmental parameters in oligodendrocytes and neurons that put the late preterm brain at risk in the broader context of brain
development and injury close to term. Further research is needed about the clinical and
pathologic aspects of brain injury in general and PVL in particular in late preterm infants to
optimize management and prevent adverse neurological outcomes in these infants that,
however subtle, may be currently underestimated.
Semin Perinatol 30:81-88 © 2006 Elsevier Inc. All rights reserved.
KEYWORDS axons, periventricular leukomalacia, prematurity, oligodendrocytes, antioxidant
enzymes
I
t has long been recognized that the majority of severely
premature born infants have poor long-term neurological
outcomes, with significant cognitive, behavioral, and/or motor deficits.1-4 In the United States alone, for example, approximately 55,000 live newborns are born very low birthweight (⬍1500 g birthweight) each year,4 and nearly 90%
survive: approximately 10% of these infants, however, later
exhibit cerebral palsy, and about 50% develop cognitive and
behavioral deficits.4 Thus, nearly 5000 cases of cerebral palsy
and 10,000 to 20,000 cases of serious learning disabilities
result each year from early premature deliveries. The common perception, on the other hand, is that “near-term” or
“late preterm” infants (variously defined as 34-37 or 35-37
gestational weeks at birth) are spared substantial brain injury,
and are neurologically “normal” or “almost normal” in the
neonatal period and beyond. (According to the general agreement of the conference participants, we will hereafter use the
word “late preterm” rather than “near-term”.) Periventricular
leukomalacia (PVL) is the most common substrate of neuro-
Department of Pathology, Children’s Hospital Boston and Harvard Medical
School, Boston, MA.
Address reprint requests to Hannah C. Kinney, MD, Department of Pathology, Enders 1112, Children’s Hospital Boston, 300 Longwood Avenue,
Boston, MA 02115. E-mail: Hannah.kinney@childrens.harvard.edu
0146-0005/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2006.02.006
logical disabilities in the very prematurely born infant.5 This
disease affects the immature white matter of the cerebral
hemispheres, and peaks at 24 to 32 gestational weeks.5 Nevertheless, it is not restricted to the very prematurely born
infant, but also occurs in the late preterm (and term) infant.6-9
Below, we review the problem of PVL in the late preterm
infant, and the maturational factors of the cerebral white
matter that put the late preterm brain at risk. We focus on the
similarities and differences to those in the very premature
brain. We begin with a general consideration of brain development and its relationship to injury in the late preterm
infant.
Brain Development and
Injury in the Late Preterm Infant
The last half of gestation is a critical period in the growth and
development of the human brain (Figs. 1–3). A “critical period” is defined as a time-sensitive, irreversible “decision
point” in the development of a neural structure or system in
which deprivation of the normal environment interrupts the
maturational trajectory of the structure/system. As a result,
there are profound consequences for later brain maturation
and behavior that cannot be corrected. Critical brain periods
are characterized by rapid and/or dramatic changes in one or
81
H.C. Kinney
82
% Full-term Brain
Weight
Human Brain Growth
100
90
80
70
60
50
40
30
20
10
0
18 20 22 24 26 28 30 32 34 36 38 40
Gestational Age (wks)
Figure 1 Brain weight at different ages from 20 to 40 (term) gestational weeks is expressed at each age as a percent of term brain
weight. Late preterm, at 34 gestational weeks, the overall brain
weight is 65% of term weight. The percent brain weights are based
on the data of Guihart-Costa and Larroche.10
more molecular, neurochemical, and/or structural parameters, such as the major “burst” of active brain growth in the
last half of human gestation (Fig. 1).10 A “vulnerable” period
is the developmental window in which the neural structure/
system is susceptible to deprivation of normal environmental
influences, or to adverse environmental factors, eg, cerebral
ischemia/reperfusion in PVL (see below). At 20 gestational
weeks, the brain weighs 10% of the brain at term; between 20
and 40 weeks, the overall brain weight increases 90% in a
relatively linear fashion (Fig. 1).10 Strikingly, the late preterm
brain at 34 weeks weighs only 65% of the term brain, with a
35% increase in growth still needed to reach term weight. At
20 to 24 gestational weeks, neuronal proliferation and migration to the cerebral cortex are considered to be complete. At
20 weeks, however, the brain is smooth, with formation only
of the Sylvian fissure; in contrast, by 40 weeks, all of the
primary, secondary, and tertiary gyri and sulci have formed
(Fig. 2). Gyral and sulcal development is still incomplete late
preterm. Volumetric magnetic resonance determinations
during late gestation also demonstrate a dramatic increase in
the volume of the total gray matter from 29 to 41 gestational
weeks, with a linear increase of approximately 1.4% or 15 mL
in absolute volume per week.11 This pronounced increase in
total gray matter volume primarily reflects a four-fold increase in the volume of the cerebral cortex.11 Of note, the
cortical volume in the very preterm infant at 28 gestational
weeks is 13% of term volume.11 Nevertheless, the cortical
volume in the late preterm infant is only 53% of the term
volume, with approximately half the volume to be obtained
in the last 6 weeks before term, ie, 40 gestational weeks. In
addition, minimal “myelinated” white matter is present in the
very preterm infant (around 29 weeks), but increases dramatically in volume as term is approached, with a five-fold increase between 35 and 41 weeks.11 Underlying the overall
growth of the brain in the last half of gestation are major
organizational events in the development of neurons and glia
at the cellular and molecular level (Fig. 2). Synaptogenesis
and dendritic arborization are occurring, and are likewise
incomplete in the late preterm brain compared with the term
brain, but not to the degree seen in the very premature brain
(Fig. 2).12 Of note, these developmental changes continue to
occur beyond the neonatal period (Fig. 2). In addition, axons
to and from the cerebral cortex undergo elongation throughout the second half of gestation and into infancy, as demonstrated by us with the marker Growth-Associated Protein-43
(GAP-43) (Fig. 3).13 GAP-43 is a major phosphoprotein of
neuronal growth cones in the developing and brain, and is
involved in axonal outgrowth among other functions.13
Thus, axonal elongation in the cerebral white matter is ongoing in both the very premature and late preterm brain, and
even in the term brain, and thus is potentially vulnerable to
injury. Of major relevance to the pathogenesis of PVL, the
maturation of oligodendrocytes and myelination are likewise
incomplete in the term brain,14-18 as discussed below.
In addition to developmental changes within the cerebral
cortex itself, there are concomitant changes in its connectivity. Subplate neurons are the earliest differentiated neurons
originating from the ventricular zone in the first trimester of
intrauterine life. They underlie the cortical plate and are actively involved in the path finding of axons from and to the
thalamus.19-24 Subplate neurons have been implicated in the
refinement of thalamocortical innervation via activity-dependent mechanisms whereby electrical activity (action potential) patterns influence the in-growing thalamocortical axons.
Ablation of subplate neurons at a specific time-point in feline
gestation (E43 in a gestation of 65 days) leads to the absence
of Layer IV of the cerebral cortex as in-growing thalamocortical axons fail to reach it.21 Depletion of subplate neurons in
Figure 2 The immaturity of the laminar position and dendritic arborization of neurons, as demonstrated by Golgi drawings, in the
cerebral cortex in the late preterm infant at 35 gestational weeks is
striking in comparison to neurons at midgestation (20 weeks) and at
term (40 weeks). The drawings by Chan and Armstrong are reprinted by permission.12
Risk for periventricular leukomalacia
83
weight by 34 weeks underscores the immaturity of the late
preterm brain and its potential vulnerability to multiple insults that interfere with basic mechanisms of neuronal and
glial maturation during this time-frame. Brain insults in the
late preterm brain can also alter the trajectory of specific
programs in neuronal and glial development, as they do in
the very premature brain, thereby contributing to the neurological disabilities of the survivors. In PVL, for example, necrosis in the cerebral white matter causes axonal injury and
deafferentiation of the overlying cerebral cortex, with subtle
secondary abnormalities in neuronal differentiation and process outgrowth.30
Definition of PVL
Figure 3 (Top) GAP-43 expression levels in the developing white
matter were examined by western blot analysis. (Bottom) These
levels were grouped according to ages reflecting epochs of human
brain development and plotted as a percent of adult human standard. GAP-43 expression in the white matter remains high, relative
to the adult standard, suggesting that axons are still growing from 19
to 64 gestational weeks.13
early postnatal life in animal models also has age-specific
detrimental effects, eg, prevention of thalamic axons into
ocular dominance columns in Layer IV of the visual cortex,23
and impairment in synaptic transmission of visually-driven
activity in the geniculocortical circuit.24 In human gestation,
the subplate neurons are first identifiable around 10 weeks,
and they peak in number from 22 to 35 gestational
weeks.25,26 Pruning of the subplate population begins around
27 gestational weeks and continues through the newborn
period.27,28 Given that subplate neurons retain electrogenic
potential and functional synaptic input postnatally, the expression of the neuromodulator nitric oxide by them supports a continued role for them in refinement and synaptic
plasticity after the cerebral cortex is formed. Selective
subplate neuronal loss occurs in a neonatal rat model of
hypoxic–ischemic injury,29 underscoring the possibility of
homologous injury in human premature infants. Damage to
subplate neurons, which may be adversely affected by surrounding white matter injury in PVL, may play a role in
altered thalamocortical axonal development and cortical innervation in this disorder, and thereby may contribute to the
cognitive deficits in long-term survivors. We emphasize that
subplate neurons are still prominent in the late preterm
brain, and that axonal interconnections between the thalamus and cerebral cortex, as assessed by the high level of
GAP-43 in the cerebral white matter,13 are likely not completely formed at this age, analogous to the preterm brain.
Thus, hypoxic–ischemic damage to the subplate neurons—
yet to be demonstrated in human PVL—may potentially contribute to cognitive deficits in late preterm, as well as preterm,
infants.
Recognition that the brain reaches only 65% of term
PVL is defined morphologically by two histopathologic components: (1) a “focal”, necrotic component in the periventricular region of the cerebral white matter; and (2) a “diffuse”
component characterized by reactive gliosis in the surrounding white matter.5 Each component has different histopathologic outcomes: (1) the necrotic foci, involving all tissue components, evolve into cysts that typically collapse and
eventually form focal scars; and (2) the diffuse lesion appears
to involve preferential injury to premyelinating oligodendrocytes (pre-OLs) in the surrounding central white matter,
leading to a global delay in myelination.5 Although the focal
necrotic lesions correlate well with cerebral palsy (motor deficits), it has been suggested that the diffuse white matter
lesion correlates with cognitive and behavioral abnormalities
observed with PVL.4 These latter disorders may also be related to concomitant injury to the gray matter, eg, cerebral
cortex, thalamus, and basal ganglia. Indeed, there is increasing recognition that PVL is associated with gray matter injury.
Neuroimaging studies have demonstrated reduced cortical
volumes in premature infants at term equivalent.1,31,32 Quantitative MRI studies in premature infants also demonstrate
reduced thalamic volumes with or without associated white
matter damage.1 MRI analysis in 119 consecutively born premature infants demonstrated that a low index of mental development (Bayley scales) at 1 postnatal year correlated most
strongly with decreased deep gray matter (thalamus and
basal ganglia combined) volume at term equivalent age.1
Our studies of the neuropathology of prematurity indicate
that neuronal loss and gliosis, albeit subtle, occurs in multiple gray matter sites, particularly the thalamus and, to a lesser
extent, the cerebral cortex.6 We found that gliosis occurs in
the thalamus in 33% of premature infants (n ⫽ 41), and
neuronal loss in this site occurs in 15%.6 Damage to the
thalamus raises the possibility of additional abnormal functioning in the cerebrocortical–subplate–thalamic “unit” comprised of thalamic neurons that project to the cerebral cortex
and the subplate neurons that are critical in the targeting of
axons between the thalamus and cortex during cortical development (see above). The thalamus plays a key role in
cognition, not only via certain nuclei relaying sensory information from the external world, but also via associative nuclei positioned as critical components of distributed neuronal
networks. The idea that an individual thalamic nucleus is a
84
critical component of a distributed neural network that subserves a particular cognitive ability is supported by clinical
observations that lesions in a specific thalamic nucleus can
result in functional impairments similar to damage in the
cortical region itself.33 Although neuronal loss and gliosis in
gray matter sites are nonspecific findings, their topography
and histopathologic features in the premature brain are consistent with hypoxia–ischemia. The finding of gliosis and
neuronal loss indicates subacute/chronic injury, and likely is
the substrate, at least in part, of reduced volumes of gray
matter structures in survivors of prematurity. We postulate
that the combined gray and white matter damage in the premature infant is due to hypoxia-ischemia, infection, and/or as
yet undefined factors in a vulnerable period in the development of OLs and neurons, and that the combined lesions in
the susceptible white and gray matter sites reflect interactions
between oxidative-, nitrative-, glutamate-, and cytokine-toxicity.
Incidence of PVL in Late
Preterm and Term Infants
The incidence of PVL in preterm and term infants is not
completely known. In our study of the neuropathology of
congenital heart disease in infants dying after cardiopulmonary bypass surgery (n ⫽ 38), the mean gestational age was
39.3 ⫾ 1.4 weeks (term), with a mean birth weight of 3126 ⫾
53 g and median postnatal age of 21 days (range: 1-398
days).7 In this cohort, the overall incidence of PVL was 61%,
with this lesion representing the most common neuropathologic finding.7 Of note, 32% of the PVL lesions were acute, ie,
characterized by coagulative necrosis without inflammatory
cell (astrocytic and microglial) reaction, a lesion considered
to be 24 to 48 hours in duration and therefore histopathologic evidence of origin in the term time-frame. PVL has also
been reported in living preterm and term infants with congenital heart disease following cardiac surgery with the use of
magnetic resonance imaging.8,9 Nevertheless, the overall incidence of PVL and long term outcome in living late preterm
infants are not known. Of relevance to the clinical outcome of
brain injury in late preterm and term infants, a recent report
from the western Swedish study of the prevalence and origin
of cerebral palsy indicated that there was a decreasing overall
trend between 1995 and 1998 in both children born preterm
and at term.34 Nevertheless, there was an increase in dyskinetic cerebral palsy in children born at term, defined in this
study as birth after 36 gestational weeks. In this group of
children with dyskinetic cerebral palsy, 71% of the cases had
hypoxic–ischemic encephalopathy in the perinatal period.34
Pathogenesis of PVL
The major causes of PVL are considered to be: (1) cerebral
ischemia/reperfusion in the critically ill premature infant
with cerebral vascular immaturity and arterial end-zones in
the periventricular region, coupled with the propensity for
impaired vascular autoregulation; and (2) bacterial infection
H.C. Kinney
in the mother and/or fetus that triggers a cytokine response in
the fetal brain, either by entry of maternal and/or fetal cytokines across the fetal blood– brain– barrier that then directly
injure pre-OLs, or by entry of bacterial components, eg, endotoxin, into the fetal brain and stimulation of the local cytokine production by microglia and/or astrocytes.5 These two
causes, ie, cerebral ischemia and infection, likely act synergistically to produce cerebral white matter damage, such that
the infant previously exposed to intrauterine infection may
be especially vulnerable to pre-OL injury by ischemic insults
that are not sufficient to cause injury alone. Of note, late
preterm infants, like very premature infants, can require
management in intensive care nurseries, and have a higher
incidence than term infants of respiratory distress syndrome,
apnea, and infection—all defined risk factors for PVL.5
In our laboratory, the over-riding hypothesis concerning
the pathogenesis of PVL is that pre-OLs are the targeted cell
population due to preferential vulnerability to free radical,
glutamate, and cytokine toxicity in the developmentally immature white matter. The genesis of the idea that pre-OLs are
targeted in PVL is the demonstration by neuroimaging studies of reduced white matter volume, ventriculomegaly, and
impaired myelination.5,35,36 In addition, human autopsy
studies report that OLs (lineage stage unknown) appear decreased and/or myelination is retarded.35 Studies in our laboratory with specific antibodies to pre-OLs (O1⫹ and O4⫹)
provide three major lines of evidence that pre-OLs are the
preferential target in the diffuse component of PVL: (1) late
progenitors (NG2⫹O4⫹) predominate in the cerebral white
matter during the peak window of PVL, ie, 24 to 32 gestational weeks, before the earliest expression of MBP⫹ (around
30-35 gestational weeks)14 (Fig. 4), and 3 to 4 months before
active myelin sheath synthesis16-18; (2) pre-OLs preferentially
die in the diffuse component of PVL as demonstrated by
double labeling with TUNEL and antibodies to O1 and O437;
and (3) there is a qualitative loss of pre-OLs in occasional
severely affected PVL cases.37 Taken together, these data suggest the possibility that injury to pre-OLs occurs in the diffuse
component of severely affected cases of PVL.
Neuropathologic studies by us and others suggest a major role for reactive nitrogen species (RNS) and/or reactive
oxygen species (ROS) in pre-OL cytotoxicity.37,38 There is
also marked activation of microglia in the diffuse component of PVL, suggesting the possibility that activated microglia are key contributors of ROS and RNS that injure
and potentially kill pre-OLs.37 In PVL, we propose that the
underlying basis of ROS and RNS generation includes cerebral ischemia/reperfusion. Of direct relevance to PVL,
data from perinatal rat models and rodent cell culture
indicate pre-OLs are preferentially vulnerable to ROS in
comparison to MBP⫹ OLs.38,39 The finding of a diffuse
activation of microglia further suggests the possibility that
ischemic and infectious insults, the latter potentially
through the activation of toll-like receptors by bacterial
products, converge to activate microglia in the inflammatory response, and thereby augment free radical production and exacerbate white matter damage that may have
been minimal with either insult alone.5
Risk for periventricular leukomalacia
Figure 4 The timing of the appearance of pre-OLs in the human
cerebral white matter (n ⫽ 18).14 At 28 to 35 weeks, an age-range
including late preterm infants at 34 and 35 weeks, the proportion of
pre-OLs (O4⫹O1⫺) is 10% greater and the proportion of immature
OLs (O4⫹O1⫹) is 10% less than that in the age-range including
term, ie, 36 to 41 weeks. These data indicate the relative immaturity
of the composition of the OL cell linage in the late preterm brain
compared with the term brain.
Maturational Factors of
the Cerebral White Matter
in the Late Preterm Infant
A major focus of our laboratory has been to determine the
developmental factors at the cellular level that underlie the
vulnerability of the fetal white matter to injury in PVL. The
first step we took in our laboratory toward understanding
these factors was to delineate the developmental profile of
OL cell lineage during the peak period of risk (Fig. 4).14 In
26 control autopsy brains, OL lineage progression was
defined by us in the parietal white matter at the level of the
atrium, a known region of predilection for PVL. Three
successive OL stages, ie, late OL progenitor, immature OL,
and mature OL, were characterized between 18 and 41
weeks with anti-NG2 proteoglycan, O4, O1, and anti-MBP
antibodies. We found that NG2⫹O4⫹O1⫺ late progenitors
were the predominate stage throughout the last half of
gestation. Between 18 and 27 weeks, O4⫹O1⫹ immature
OLs were a minor population (9.9 ⫹ 2.1% of total OLs, n
⫽ 9) (Fig. 4). Between 28 and 41 weeks, an increase in
immature OLs to 30.9 ⫹ 2.1% of OLs (n ⫽ 9) was accompanied by a progressive increase in MBP⫹ myelin sheaths
that were initially restricted to the periventricular white
matter, and first detected by immunocytochemistry
around 30 weeks. Thus, the developmental window of the
peak occurrence of PVL precedes the onset of active myelin sheath synthesis, ie, the time-frame when the late progenitors (NG2⫹O4⫹O1⫺) predominate in the cerebral
white matter. The predominance of one major population
of pre-OLs during the peak period of risk for PVL suggests
that this OL stage is the potential target for injury in the
diffuse component of PVL. Moreover, the decline in the
incidence of PVL beyond late gestation coincides with the
first appearance of MBP⫹ OLs, followed by active myelin
sheath synthesis in early infancy. These data suggest that
differentiation of pre-OLs to mature OLs underlies the
85
increased resistance of the mature cerebral white matter to
ischemia/reperfusion. Yet, in considering the occurrence
of PVL in the late preterm brain, it should be emphasized
that pre-OLs still dominate the late preterm cerebral white
matter and active myelin sheath synthesis with MBP production has yet to occur (Fig. 4).14 Indeed, active wrapping of axons by the myelin sheath, does not occur in the
cerebral white matter until 3 to 5 postnatal months.16-18
Understanding the precise timing of the sequences of myelination in the developing cerebral white matter helps to
explain the vulnerability of the late preterm, as well as very
premature brain to PVL. Recognition of the different stages
of pre-OL differentiation and active myelin sheath synthesis across the last half of gestation, with more advancement
in the late preterm than very premature brain, also helps
explain the increased vulnerability of the very premature
compared with the late preterm brain.
In our laboratory, we tested the hypothesis that the
vulnerability of pre-OLs to free radical attack results, at
least in part, from a relative developmental lack of the
antioxidant enzymes (AOEs) in the cerebral white matter
during the peak period for PVL in the very premature
infant.40 We analyzed the developmental profile of selected AOEs (catalase, copper/zinc-containing superoxide
dismutases [CuZnSOD], manganese-containing superoxide dismutases [MnSOD], and glutathione peroxidase
[GPx]) in the cerebral white matter of the human brain
from midgestation through the perinatal period40 (Fig. 5).
During the period of greatest PVL risk (24-32 gestational
weeks) and through term, including late preterm, we
found that expression of both SODs (necessary for conversion of superoxide to hydrogen peroxide), as determined
by western blot analysis, significantly lagged behind that
of catalase and GPx (necessary for breakdown of hydrogen
peroxide), which, in contrast, superseded adults levels by
30 weeks (Fig. 5). Animal studies indicate that the balance
of all the AOEs in the brain must be optimized for proper
protection from oxygen free radicals in hypoxic–ischemic
injury, with the caveat that this balance may differ between the mature and immature brain.40 Thus, the developmental lag in the expression of the SODs relative to
catalase and GPx represents, in our opinion, a likely crucial “rate-limiting” factor in the protection of pre-OLs from
superoxides.
Additional factors that likely contribute to the vulnerability of the fetal cerebral white matter to ischemic/inflammatory injury that we and others have found in autopsy in
studies of the brains of premature and term infants include:
(1) transient over-expression of AMPA receptors on preOLs41; (2) transient over-expression of the EAAT2 glutamate
transporter, with documented expression in pre-OLs42; (3)
transient over-expression of activated microglial density43;
and (4) immaturity of the vasculature of the deep and
periventricular white matter. Clearly there is no single factor,
but rather, a convergence of multiple factors that accounts for
the maturational vulnerability of the fetal white matter to
hypoxic–ischemic injury.
H.C. Kinney
86
Percent of Adult Standard
0 50 100 200 300 400 500
600
Developmental Milestones of Antioxidant Enzyme Expression
Copper-Zinc SOD
Catalase
MnSOD
Summary Points
Brain Size
● The brain volume increases at a rate of ⬃15 mL
(1.4%) per week between 29 and 41 weeks of gestation.
● At 28 weeks of gestation, the brain is ⬃13% of term
brain volume; by about 34 weeks of gestation, the
volume is ⬃65% of term brain.
● Thus, more than one-third of brain size increase
takes place during final 6 to 8 weeks of gestation.
Glutathione Peroxidase
20
20
|
midgestation
30
30
|
40
40
|
50
50
60
60
Term Birth
Postconceptional Age (weeks)
Figure 5 Antioxidant enzyme expression differs with age for MnSOD, CuZnSOD, and catalase (all, P ⬍ 0.001), but not for GPx (P ⫽
0.516).40 At term (vertical dotted line), SOD levels are less than
adult levels (horizontal dotted line [100%]), in contrast to those of
catalase and GPx. The levels of the dismutases are intermediate
between very preterm and term levels. After term, the CuZnSOD
level markedly increases, and coincides with the postnatal period of
active myelin sheath synthesis and physiologic levels of lipid peroxidation in myelin production.
Summary
In summary, different events in cerebral white and gray matter development, eg, OL differentiation, myelination, antioxidant enzyme production, gyration, synaptogenesis, and axonal elongation, follow different sequences of maturation
with different tempos in the human brain over the last half of
gestation, thereby defining differential periods of vulnerability to injury. The maturation of the cerebral white matter is
incomplete in the late preterm brain, and thus it is vulnerable
to PVL, as established by the documentation of PVL in the
late preterm (and term) brain in neuroimaging and autopsy
studies. Yet, the peak of PVL occurs in the very premature
infant, and likely reflects, at least in part, a greater degree of
immaturity of the various factors that put the white matter at
risk. Indeed, the increasing advancement in the developmental confluence of cellular and molecular factors in the cerebral
white matter helps explain the “hierarchy of vulnerability” to
PVL, with the greatest vulnerability in the very premature
brain, followed by the late preterm and term brain, and the
greatest resistance in the heavily myelinated brain in infancy
and beyond. Nevertheless, developmental programs may not
all be “linear” in their trajectory, and thus, the development
of different parameters may “peak” at different times, and not
just simultaneously at one particular age. Given the substantial overall maturation still to be undergone by the late preterm brain, injury at this time-point also has the potential to
adversely affect the trajectory of different developmental programs, with lasting consequences for neurological disabilities
in survivors.
More research is needed about the neurochemical, cellu-
Brain Structure
● A five-fold increase in white matter volume occurs
between 35 and 41 weeks of gestation.
● Structural maturation during late preterm gestations
include, increasing in neuronal connectivity, dendritic arborization and connectivity; increasing in
synaptic junctions; and maturation neurochemical
and enzymatic processes augmenting growth and
maturation of the brain.
Pathology
● Systematic ultrasound scanning of newborn head is
not done; thus the incidence of PVL is unknown in
the late preterm infant population.
● Because of early discharge and little follow-up, the
prevalence of other brain pathologies in this population remains unknown.
● An autopsy study of term infants dying after surgery
for congenital heart diseases revealed an incidence of
PVL to be 61%.
● This indicates that albeit rarely, term and late preterm infants can develop PVL, and their brains remain vulnerable for white matter injury.
Vulnerability
● The notion of “hierarchy of vulnerability” should be
understood in evaluating brain injury in the late preterm infants.
● This means that although they are more mature than
very preterm infants, their brain is still immature,
and can be damaged under appropriate adverse
conditions.
Research Needs
● Basic science to understand brain maturational sequences during the last third of gestation.
● Clinical and pathology studies on epidemiology of
brain injury in this group.
● Long-term developmental outcome of late preterm
infants.
lar, and molecular development of the human brain at the
end of gestation. We need to define in particular the sequences of neuronal and glial maturation by week-to-week
dates from 34 to 40 gestational weeks. Given the applicability
Risk for periventricular leukomalacia
of modern tools in neuroscience to the study of the human
brain at autopsy, this goal is attainable, and its fulfillment will
greatly aid in our understanding of the factors that put the
late preterm human brain at risk for multiple types of insults.
More information is also needed about the incidence and
long-term neurological outcome of PVL and gray matter
damage in late preterm infants, as distinct from very premature and term infants. Finally, research is needed about the
long-term neurological outcome of healthy infants born at
34, 35, and 36 gestational weeks compared with infants born
at 39 to 40 weeks. The under-appreciated degree of immaturity of the late preterm brain relative to the term-brain begs
the question: does the apparently healthy late preterm infant
demonstrate compromised cognitive, behavioral, and/or motor skills, however subtle, at school age and beyond? Underlying this question is concern about potential (unknown)
detrimental effects on brain development of extrauterine
compared with intrauterine life during the last 3 weeks of
gestation, ie, from 34 to 37 gestational weeks, when the brain
is still undergoing rapid and dramatic development. The answer to this question is crucial to our ultimate understanding
of the impact of birth close to, but not at, our current definition of term.
Acknowledgments
The author appreciates the assistance of Mr. Richard A. Belliveau in manuscript preparation, and of Drs. Robin L.
Haynes and Joseph J. Volpe in critical reading of the manuscript. This work is supported by the National Institute of
Neurological Disorders and Stroke (PO1-NS38475) and
Children’s Hospital Boston Mental Retardation Research
Center (P01-HD18655).
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