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Handbook of Clinical Neurology, Vol. 111 (3rd series)
Pediatric Neurology Part I
O. Dulac, M. Lassonde and H.B. Sarnat, Editors
© 2013 Elsevier B.V. All rights reserved
c0080
Chapter 16
Pathophysiology of cerebral palsy
1
STEPHANE MARRET 1, 2*, CATHERINE VANHULLE 1, AND ANNIE LAQUERRIERE 2, 3
Department of Neonatal Medicine and Centre of Child Functional Education, Rouen University Hospital, Rouen, France
2
Microvascular endothelium and neonatal brain damage Research Team, Rouen Institute for Medical Research and Innovation,
School of Medicine, Rouen University, France
3
Pathology Laboratory, Rouen University Hospital, Rouen, France
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Cerebral palsy (CP) is a range of nonprogressive syndromes
of posture and motor impairment, causing activity limitation, and often accompanied by other neurodevelopmental
disorders such as specific cognitive or visual deficits (Bax
et al., 2006). Nearly half of these disabilities are diagnosed
in preterm born children and the other one in full-term born
children (Expertise INSERM, 2004). CP is usually classified into topography-based subtypes (quadriplegia, diplegia, hemiplegia, or extrapyramidal disorders) which
often result from various insults to different areas within
the developing nervous system, occurring in utero, during
delivery, or after birth during the first 2 years of life. The
vulnerability of different brain structures and types of disability associated with CP are strongly influenced by the
gestational age at which brain development is altered. Better insights into the mechanisms of sub-type CP occurrence
are urgently needed to lead to brain protection strategies
and CP prevention as changes in obstetrical practice and
the development of neonatal care over the last 25 years have
had little effects on the rate of CP (Nelson, 2008).
CAUSAL FACTORS
Human population-based epidemiological studies and
neuroimaging, in particular resonance magnetic nuclear
imaging (MRI), are the best ways of identifying physiopathogenesis of the different subtypes of CP.
In the first part of pregnancy until 24 weeks’ gestation,
cortical neurogenesis takes place and is characterized
by proliferation, migration, and organization of neuronal
precursor cells, then neurons. It can be altered by
genetic deficits or acquired (viral or toxic) impairments
resulting in rare malformations such as lissencephaly or
agyria-pachygria, nodular heterotopias, polymicrogyria,
schizencephaly, and cortical dysplasia.
In the second part of pregnancy, growth and differentiation events (axonal and dendrite growth, synapse
formation, and myelination) as well as stabilization processes (neural cell apoptosis, neurite regression, redundant synapse elimination) and specialization of circuitry
are predominant and persist after birth and are maximal
during the first 2 years of life. Environmental factors such
as hypoxiaischemia are involved in the occurrence of CP
at this step of brain development. These factors could be
severe enough to determine destructive injuries visible
using standard imaging (i.e., ultrasonographic study or
MRI), predominantly in the white matter of preterm infants and in the gray matter and the brainstem nuclei
of full-term newborns. Moreover, they occur in an immature brain and could alter the remarkable series of developmental events. CP is therefore the result of destructive
and developmental mechanisms.
Interruption of oxygen supply to the fetus and brain
asphyxia were classically considered to be the main
causal factors explaining later CP. But clinically defined
birth injury or birth asphyxia account for a minority of
cases of CP. Several nonischemic factors have now been
recognized in human epidemiological studies and in animal experimental studies (Fig. 16.1). CP is infrequently
due to a brain malformation secondary to a unique genetic deficit or an acquired perinatal damage due to a
unique acute asphyxic event (Fig. 16.2). In most cases
of CP, causal factors do not act in isolation, but in
synergy to create a disturbance. A set of predisposing
*Correspondence to: Stéphane Marret, Department of Neonatal Medicine and Centre of Child Functional Education.
Rouen University Hospital, 1 Rue de Germont, F-7600 Rouen, France. Tel: þ.33.2.32.88.80.97, Fax: þ .33.2.32.88.86.33, E-mail:
[email protected]
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2
M. STEPHANE ET AL.
Causal factors of cerebral palsy between 20 weeks of gestation
and neonatal period
Predisposing
factors
Acute or subacute perinatal factors
• Preterm birth
• IUGR
• Vascular disease
of pregnancy
• Hormon or
Growth factor
deficiency
• Toxic – In utero
stress
• Hypoxic-IschemiaReperfusion
• Infection-Inflammation
Post-natal
factors
• Chronical
hypoxia
• Drugs
• Nutrition
• Mother/baby
separation
• Socio-economic
level
●
Window for prevention
Developmental
disorders
Destructive lesions
Window for repair
Motor and cognitive disabilities
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Fig. 16.1. Causal factors of cerebral palsy between 20 weeks
of gestation and neonatal period.
antenatal factors, perinatal acute or subacute events,
and postnatal aggravating factors act together on the
developing brain of the fetus and the newborn to alter
brain maturation and lead to CP.
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Predisposing factors
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Predisposing antenatal factors include various genetic,
epigenetic, and environmental factors:
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Congenital abnormalities. There is a consistent observation that children with CP have more congenital
abnormalities (cleft lip and palate, hypospadias, gut
atresias. . .) than other children (Pharoah, 2007).
Genetic factors. They could influence the risk of CP
along the cascade of events leading to CP. An
increased risk of CP has been observed in some
families in a national Swedish database (Hemminki
et al., 2007). Genetic factors are involved in some
thrombophilias underlying perinatal strokes and
secondary CP (Kirton and de Veber, 2009). But it
has been suggested that most thrombophilias need
another event such as viral or bacterial infection to
cause vascular thrombosis (Gibson et al., 2003).
Genetic polymorphisms in gene encoding proteins
of inflammation or coagulation or vascular endothelium of the placenta are associated with CP in some
children (Nelson, 2008).
Infections. Among the congenital TORCH (Toxoplasma (Fig. 16.2A), Other (syphilis, varicellazoster, parvovirus B19, Rubella, Cytomegalovirus
(CMV), Herpes simplex virus) infections, CMV is
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the most frequent virus implicated in brain damage
during pregnancy. Congenital enterovirus, arenavirus, and lymphocytic choriomeningitis virus infections are exceptional. Moreover it has been shown
that fetal exposure to a variety of viruses may be associated with hypertensive pregnancy disorders and
that perinatal exposure to neurotropic viruses is associated with preterm delivery and cerebral palsy
(Gibson et al., 2003).
Toxic factors. Alcohol is one of the most frequent
toxic factors which could determine brain maldevelopment during the whole pregnancy and later CP
in case of severe malformation such as lissencephaly
(Guerri, 2002). In animal studies, it was observed that
it is an additional factor which aggravates damage induced by an acute ischemic or excitotoxic event
(Adde-Michel et al., 2005). The role of other maternal
types of drug abuse, such as cocaine, seems to be less
important than previously thought (Bauer et al.,
2005). An increasing number of drugs such as valproic acid taken by the mother during gestation are
shown to interfere with brain energy, transport of
monocarboxylic acids, and carbohydrate and lipid
metabolisms. This alteration may not be transitory
but can permanently impair fetal neuronal function
and contributes to postnatal neurological disease
including CP (Bolanos and Medina, 1997).
Multiple gestation. The higher risk of CP observed
in this population is due to two main factors: the high
rate of preterm birth and co-twin death whether they
were same-sex or not. In monozygotic twins, where
one twin dies, vascular collapse in the survivor or an
embolism originating from the circulation of the dead
twin can occur resulting in encephalomalacia or
porencephaly and secondary CP (Scher et al., 2002).
Vascular disease of pregnancy. Preclampsia and intrauterine growth restriction have been demonstrated to be associated in several epidemiological
studies with neonatal encephalopathy in full-term
newborns and subsequent CP (Badawi et al., 1998).
Preterm birth. Separation of the fetus from his natural environment before the end of gestation could
alter the normal development of the brain (Livinec
et al., 2005). It was demonstrated in animal models
that some maternal or placental factors such as
vasointestinal peptide act early on the fetal neural
axis to stimulate their development (Gressens
et al., 1993).
Post-term birth. Placental involution which begins
in cases of postmaturity makes the brain sensitive
to damage (Badawi et al., 1998).
Maternal factors. Maternal thyroid disease has
been related to neonatal encephalopathy and CP in
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reviewer(s), Elsevier and typesetter SPi. It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is
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PATHOPHYSIOLOGY OF CEREBRAL PALSY
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Fig. 16.2. Macroscopic views of fetal or neonatal cerebral lesions. (A) Coronal section of a fetus with first trimester pregnancy
toxoplasma infection. (B) Unilateral schizencephaly in a fetus whose mother had had an interruption of pregnancy. (C) Periventricular leukomalacia with multicavitary lesions in an infant born at 30 weeks’ gestation. (D) Putamen necrosis in an at term newborn with perinatal asphyxia.
●
full term infants as well as other factors such as
lengthy maternal menstrual interval or diabetes
(Nelson, 2008).
Sex. A recent emerging concept is that sex may influence the pathogenesis of developmental brain injuries. CP is more prevalent in males than in females.
Males with preterm birth had significantly reduced
white matter compared with term males while white
matter was equivalent in female groups. In contrast
preterm females with intraventricular hemorrhage
(IVH) showed a reduction in gray matter compared
with controls, but males with IVH did not (Johnston
and Hagberg, 2007).
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Acute perinatal events
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Birth asphyxia can cause spastic diplegia in very preterm
infants and quadriparetic CP with mental retardation
from 34 weeks’ gestation at birth. The criteria promulgated by the American College of Obstetricians and Gynecologists and American Academy of Pediatrics to
attribute intrapartum hypoxia as a cause of neonatal encephalopathy and later CP in full-term newborns include:
(1) an umbilical arterial pH of 7; (2) a moderate or severe neonatal encephalopathy; (3) a later quadriparetic or
dyskinetic CP; and (4) an absence of other causes. However CP is seldom preceded by an intrapartum event. The
proportion of CP associated with an intrapartum event
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4
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M. STEPHANE ET AL.
was found to be 14.5% in a review of the literature in the
English language (Graham et al., 2008).
Inflammation, maternal fever caused by chorioamnionitis, or urinary tract infection are now well-recognized
subacute or acute factors frequently associated with neonatal encephalopathy at birth and with CP risk in several
studies regarding preterm, near-term, or full-term infants
(Nelson and Grether, 1997; Wu et al., 2003; Bax et al.,
2006). In a study of full-term newborns who had CP
and for whom genetic and viral pathogenic causes were
excluded, 38% of spastic quadriplegia was associated with
chorioamnionitis (Wu et al., 2003).
Many studies have linked the close associations between perinatal infections and hypoxicischemic insults.
Infection/inflammation can potentiate hypoxicischemic
insults to the brain and convert a subthreshold insult to a
seriously damaging event. But some animal studies did
not yield support for the hypothesis that brain damage
is due to reduced blood flow in infection (Duncan
et al., 2002; Girard et al., 2009).
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Postnatal additional factors
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These factors are mainly observed in preterm infants
in whom the brain after birth is subjected to early
influences that are different from those of the
materno-placental unit. Several of these factors could
dramatically alter brain development, such as stress and
separation of mother/baby, nutrition and extrauterine
growth retardation, nosocomial infections, enterocolitis,
or drugs. The Newborn Individualized Developmental
Care and Assessment Program (NIDCAP), which notably
takes into account parental and child stress, has beneficial
effects in the short term, as it favors an early discharge
from hospital (Als et al., 2003). Postnatal infections, enterocolitis, as well as early postnatal use of glucocorticoids in preterm infants have been demonstrated to be
independently associated with white matter injury and
later CP (Glass et al., 2008; Shah et al., 2008; Halliday
et al., 2009).
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Socioeconomic status
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There is conflicting evidence in the literature regarding
socioeconomic differences in families giving birth to
children that develop CP. But most recent studies suggest
a link between CP and socioeconomic indicators. In a
Swedish study, there was a linear association between
the incidence of CP (after exclusion of head injuries, chromosomal aberrations, and brain malformations) and socioeconomic status (SES) of the household of the
mother (low SES versus high SES adjusted odds ratio
1.36 (1.051.71)) (Hjern and Thorngren-Jerneck, 2008).
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Finally it is also observed that a significant number of
children with CP experienced none of the causal factors
outlined above.
NEUROPATHOLOGICAL AND
HISTOLOGICAL ASPECTS OF
PERINATALLYACQUIRED CEREBRAL
PALSY IN PRETERM AND FULL TERM
NEWBORNS
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Neuropathological and functional aspects
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Understanding the development of the immature brain
has led to the theory of selective vulnerability, resulting
in two main distinctive associations: white matter injury
in premature infants and gray matter lesions, in particular of the basal ganglia in full-term neonates presenting
with perinatal asphyxia.
In full-term infants, hemiplegia is observed in cases
of antenatal porencephaly/unilateral schizencephaly
(Fig. 16.2B), and perinatal arterial ischemic or hemorrhagic stroke. Fetuses and neonates often have larger infarcts than adults and develop cystic lesions rather than
dense gliotic scars. One reason is that the full-term neonate has only one-sixth as many resident astrocytes in the
white matter compared with the adult. Thus astrocytic
invasion of the infarcted tissue cannot occur, resulting
in cavitary lesion. Quadriplegia or dyskinesia are most often the consequence of diffuse basal ganglia and thalamic
damage (Fig. 16.2D), cortico-subcortical injury, and/or
watershed pattern damage. A disorder of cortical development is rarely observed: abnormal proliferation and
neuronal generation as observed in microcephaly, abnormal neuronal migration as noted in type I lissencephaly
spectrum or absence of extracellular matrix integrity as
in type II lissencephaly, or “cobblestone syndrome”
(Francis et al., 2006).
In preterm infants, spastic diplegia is the most frequent motor sequela and is significantly associated with
diffuse white matter injury with intraparenchymal hemorrhage and/or periventricular cavitary lesions (Fig. 16.2C).
These damages are favored by the vascular anatomical developmental step observed in these infants who have
larger microvascular territories with poorly developed
collateral circulation compared with the adult brain, as
well as immaturity of cerebral blood flow autoregulation
(partly due to neurogenic immaturity and partly due to the
fact that the formation of smooth muscular walls of intracerebral arterioles develop late during gestation, so that
even if the neural mechanism is in place, the end-organ
cannot respond well in prematurity).
Disruption of the corticospinal tracts is responsible
for the developmental motor disorders since it is the final
pathway for mediating the influence on motoneurons of
the brainstem and spinal cord of nearly all cerebellar
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PATHOPHYSIOLOGY OF CEREBRAL PALSY
p0135
efferents and those of the basal ganglia (all via intermediate relay in the thalamus). There are no direct cerebellospinal, striatospinal, or pallidospinal tracts in humans,
explaining the dyskinesias and cerebellar deficits experienced by some children, superimposed upon their spastic
or hypotonic diplegia. The cerebellum and basal ganglia
are also influential in determining final passive muscle
tone in cerebral palsy.
But in children with CP, brain lesions are highly variable. In a cross-sectional, population-based study conducted in eight European study centers, 11.7% of 351
children with CP had normal MRI findings, the others
having white matter injury (42.5%), basal ganglia lesions
(12.8%), cortico-subcortical lesions (9.4%), focal infarcts
(7.4%), miscellaneous lesions (7.1%), and malformations
(9.1%) (Bax et al., 2006). More than half of these children
with CP were delivered at full term, while 18.3% were born
between 32 and 36 weeks of gestation, 16% between 28
and 31 weeks, and 10.9% below 28 weeks. Almost one
in five children were small for gestational age (< 10%).
In the population-based EPIPAGE study of all 2901 live
births between 22 and 32 completed weeks of gestation
observed in nine regions of France in 1997, 29.4% (46)
of the 156 children who had CP at 5 years of age had
no ultrasonographic abnormalities in the neonatal period
(Beiano et al., 2010). The ultrasonographic abnormalities
in the other 110 children with CP were as follows: 49% (77)
with white matter injury (periventricular cyst or persistent
hyperechogenicities or intraparenchymal hemorrhage),
8.9% (14) with intraventricular hemorrhage (IVH) with dilatation, 8.3% (13) with IVH without dilatation, and 3.8%
(6) with only a subependymal hemorrhage.
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MICROSCOPIC ALTERATIONS
s0045
Cerebral lesions in the preterm infant
p0140
A window of enhanced vulnerability of white matter between 24 and 34 weeks of gestation is related to the active
growth of cerebral pathways. It is a phase of high proliferation, migration, and maturation of glial cells (astrocytes and oligodendrocyte precursors) and of high
expression of microglial cells (Billiards et al., 2006).
During this period, the cortical subplate contains two
types of neurons: GABAergic neurons, which originate
from progenitors generated in the ventricular zone
and the subventricular zone of the dorsal forebrain or
of the ganglionic eminences of the ventral telencephalon, and are migrating respectively radially and tangentially toward the upper cortical layers, and subplate
neurons, which serve as sites of synaptic contacts for
“waiting” thalamo-cortical and commissural/association
cortico-cortical afferents, before entering the cortex to
form the thalamo-cortical and cortico-cortical tracts
(Petanjek et al., 2009; Volpe, 2009). An endogenous
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5
transient subplate circuitry coexists with thalamocortical permanent circuitry.
Animal and human data suggest that injury specifically
to preoligodendrocytes accounts for subsequent myelination defects after periventricular white matter injury
(McQuillen and Ferriero, 2004; Volpe, 2009). Axonal injury
and degeneration have been observed in the focal necrotic
component and the diffuse component of human white
matter injury. Moreover neuronal death and gliosis are
common in the subplate, the basal ganglia, and the cerebellum. Neuronal loss of GABAergic neurons in the subplate
has been noted in autopsy studies of human preterm newborns with periventricular leukomalacia (Robinson et al.,
2006). Contrary to thalamic and basal ganglia neurons,
which are vulnerable and often damaged, cortical layer
neurons are still immature and less sensitive to hypoxic injuries. But a huge increase in cerebral cortical volume is
documented due to an increase in volume of the neuropil
of the cortex characterized by acceleration of dendritic differentiation and arborization, development of synapses,
later-arriving GABAergic neurons, and proliferation of
glial cells and processes. Since GABAergic neurons contribute to the thickness of upper cortical layers, the overall
diminution of GABAergic neurons noted in the subplate
could have important later structural and functional
consequences. Moreover, the germinative zones are
characterized by a high angiogenesis and a propensity to
hemorrhage due to high expression levels of cyclooxygenase and vascular growth factor. The hemorrhage destroys the germinative zone and the associated venous infarction (intraparenchymal hemorrhage) damages the
dorsal telencephalic subventricular zone and the overlying
cerebral white matter. The consequences are a destruction
of white matter axons, a loss of pre-oligodendrocytes, an
interruption of thalamo-cortical axons, and an impairment
of the development of the overlying cortical plate.
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Cerebral lesions in the full-term brain
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An enhanced gray matter vulnerability is observed at this
step of brain development which is characterized by rearrangement of intracortical fibers and development of
columnar circuitry, explosive formation of synapses, retraction of exuberant callosal axons, and growth of long
cortico-cortical pathways stops (Kostovic and JovanovMilosevic, 2006).
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BIOCHEMICAL ASPECTS OF
PERINATALLY ACQUIRED CELL
DEATH AND PROCESS LOSS AND
DEVELOPMENTAL DISORDERS
Even if CP is most often caused by the interaction of several factors, it is likely that, whatever the causal factors,
it results from common pathophysiological mechanisms.
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6
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M. STEPHANE ET AL.
Key factors originating in cell death or cell process loss,
observed in hypoxicischemic as well as in inflammatory conditions, consists of excessive production of
proinflammatory cytokines, oxidative stress, deprivation of growth factors, extracellular matrix modification, and excessive release of glutamate, triggering the
excitotoxic cascade. In preterm newborns, all these
mechanisms result in a primary defect in myelination,
gliosis, and thalamic degeneration with secondary cortical and thalamic maldevelopment. Microglial cells are
the first elements to respond after any kind of injury.
They could mediate neurotoxicity as they express both
metabotropic and ionotropic glutamatergic receptors
and adenosine receptors, which have been involved in
the inflammatory response (Tahraoui et al., 2001;
Pocock and Kettenmann, 2007). Oxidative stress and
glutamate excitotoxicity account for the selective
vulnerability of oligodendrocyte progenitor cells, which
express the a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor on their soma and the
N-methyl-D-aspartate (NMDA) receptor on their processes (Karadottir and Atwell, 2007; Manning et al.,
2008; Bakiri et al., 2009). Disturbances in the distribution
of extracellular matrix, and cell or process death which
produce axonal guidance molecules within the subplate
zone and periventricular crossroads of growing axons,
are important factors involved in the alteration of the development of cortical connections in preterm newborns
(Kostovic and Jovanov-Milosevic, 2006).
In full-term newborns, similar mechanisms induce a
primary cortical and basal ganglia neuronal injury. During the immediate phase of reperfusion following diffuse hypoxiaischemia, the cellular energy failure
induces in turn a failure of the Na þ/K þ ATPase pump,
leading to depolarization of neurons, allowing the influx
of Na þ and Ca2 þ water into the cell. The cytotoxic
edema leads to cell death apoptosis or necrosis
uckman et al., 2001). Moreover, excitotoxicity is
(Gl€
due to the failure of energy-dependent reuptake of glutamate, the main excitatory neurotransmitter of the
CNS, located at the presynaptic terminal and in the postsynaptic membranes at synapses in the brain. It promotes
further influx of water by opening Na þ/K þ channels
such as the AMPA receptor as well as Ca2 þ influx via
the NMDA receptor. Glutamate receptors are developmentally regulated in both neurons and glia. Glutamatergic synaptic transmission is largely NMDA mediated
during development. NMDA receptor density peaks in
the early neonatal period followed by a peak in AMPA
receptor density. The NMDA glutamate receptor is the
predominant mediator of calcium-mediated excitotoxicity in neonatal hypoxicischemic brain injury, mainly
through activation of neuronal nitric oxide synthase.
The increase in Ca2 þ promotes free radical production,
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cell membrane damage, and mitochondrial dysfunction,
and mediates activation of genes involved in apoptosis.
The first phase of cell death occurs immediately following the insult, and corresponds to the primary necrosis of
neurons and glial cells. The second phase of cell death
occurs hours or days following severe or irreversible injury, corresponding to the delayed form of cell death,
known as apoptosis. Ischemia and many other acute,
subacute, and chronic neurological processes trigger
apoptosis by stimulating caspase or BAX activation,
release of mitochondrial cytochrome C, upregulation
of FAS death receptor, calpain activation, and PARP
( poly(ADP-ribose) polymerase) overactivation (Vexler
and Ferriero, 2001). Other neurotransmitters such as
acetyl-cholinergic or adenosine A2a receptors in microglia have also been implicated in these pathological
pathways.
The vulnerability of gray matter could e also be
explained by the fact that in near full term there is a progressive functional maturation of GABAergic hyperpolarization allowing inhibition of neurotransmission
parallel to the maturation of the KCC2 transporter expression with a laminar pattern of cortical development
(Kostovic and Jovanov-Milosevic, 2006) and also by the
fact that transient inhibition of NMDA receptors causes
massive age- and region-dependent neuronal death in
P0-P14 rat pups (Marret et al., 1995; Ikonomidou et al.,
1999). This effect is specific for NMDA blockade and occurs during a stage of ontogenesis coinciding with a period of NMDA receptor hypersensitivity (Ikonomidou
et al., 1989).
Sex-dependent cell death pathways have been demonstrated in in vivo and in vitro models of hypoxiaischemia
and oxidative stress. Males may be more vulnerable
to glutamate-mediated excitotoxicity leading to
PARP-1 activation and transfer of apoptosis-inducing
factor (AIF) into the nucleus, which triggers apoptosis.
Females are more vulnerable to oxidative stress, release
of cytochrome C from mitochondria, and activation
of caspase 3 to produce apoptosis (Johnston and
Hagberg, 2007).
In the hypoxic newborn mouse brain, a global dyssynchrony in the maturation program was observed: an accentuation of genes subserving presynaptic function
contrasts with a suppression of genes involved in synaptic maturation, postsynaptic function and neurotransmission. Alteration in genes controlling myelination
and cytoskeletal organization contributing to synapse
maturation and neural transmission, enhancement of
proapoptotic genes such as caspase 3, upregulation by
hypoxia-inducible factor-1a (HIF1a) of vascularendothelial growth factor and its receptor flk-1 responsible for stimulation of angiogenesis, altered vascular permeability, notably in the subependymal zones, and
p0165
p0170
p0175
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PATHOPHYSIOLOGY OF CEREBRAL PALSY
modification in neural differentiation were also observed (Curristin et al., 2002).
CONCLUSION
s0060
p0180
TS1
TS2
The development of cerebral palsy can be considered the
result of a remarkable series of events that occur in the
brain during its development, combining injury that is
visible on MRI and developmental disturbance. Understanding all the pathways involved in cerebral palsy is
crucial as it is likely that only a cocktail of molecules
acting on different targets could prevent it.
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Au2
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Non-Print Items
ABSTRACT
Au1
Cerebral palsy (CP), defined as a group of nonprogressive disorders of movement and posture, is the most common
cause of severe neurodisability in children. Understanding its physiopathology is crucial to developing some protective
strategies. Interruption of oxygen supply to the fetus or brain asphyxia was classically considered to be the main causal
factor explaining later CP. However several ante-, peri-, and postnatal factors could be involved in the origins of CP
syndromes. Congenital malformations are rarely identified. CP is most often the result of environmental factors,
which might interact with genetic vulnerabilities, and could be severe enough to cause the destructive injuries visible
with standard imaging (i.e., ultrasonographic study or MRI), predominantly in the white matter in preterm infants and
in the gray matter and the brainstem nuclei in full-term newborns. Moreover they act on an immature brain and could
alter the remarkable series of developmental events. Biochemical key factors originating in cell death or cell process
loss, observed in hypoxicischemic as well as inflammatory conditions, are excessive production of proinflammatory
cytokines, oxidative stress, maternal growth factor deprivation, extracellular matrix modifications, and excessive release of glutamate, triggering the excitotoxic cascade. Only two strategies have succeeded in decreasing CP in 2-yearold children: hypothermia in full-term newborns with moderate neonatal encephalopathy and administration of magnesium sulfate to mothers in preterm labor.
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