The significant improvement in the intensive care of very low weight
newborn babies has made increased survival rates possible for these
premature infants and, as a result, certain pathologies that had
previously received little attention have become the objects of
increasing interest. The principle short-term morbidities related
with premature birth are: hyaline membrane disease (HMD), bronchopulmonary
dysplasia, sepsis, necrotizing enterocolitis, patent ductus arteriosus,
retinopathy of prematurity, periventricular-intraventricular hemorrhage
(PVIVH) and periventricular leukomalacia (PVL) ().
There are many possible cerebral injuries in premature newborns
and PVIVH continues to be the most described and best known, in
particular that of the germinal matrix, which can progress, in the
most serious cases, to bleeding into the adjacent ventricular system
or the periventricular white matter ().
Such hemorrhagic injuries, in common with parenchymal hemorrhagic
infarction, are most common among preterm newborns whose gestational
ages were less than 28 weeks at birth ().
Periventricular leukomalacia occurs in between 7 and 26% of premature
infants with birth weights below 1,500 g with cerebral palsy (CP)
being a very common result. Its incidence increases in line with
reductions in mortality rates for very low weight neonates ().
The risk of these morbidities occurring is inversely related to
birth weight and gestational age. The significance of PVIVH and
PVL to the prospects for very low birth weight infant neuropsychomotor
development has become more obvious as diagnostic methods have become
more sophisticated and clinical and epidemiological findings have
become better known ().
Those extremely premature infants that survive beyond the neonatal
period present an elevated risk of neurodevelopment abnormalities
over the long term. The incidence of CP is approximately, two newborn
babies out of every 1,000 live births. While the majority of CP
cases are among full term infants after a hypoxic-ischemic cerebral
insult or other unidentifiable etiology, extremely premature infants
have a 40 times greater relative risk of developing CP ().
It is worth bearing in mind that, for the present review, we defined
extreme prematurity as a gestational age of less than 28 complete
weeks and/or birth weight of less than 1,000 g.
Ischemic brain injuries that involve the immaturity of the infant
brain are morbidities that are of great significance during this
period and merit a detailed review. The current article covers certain
conceptual definitions, the pathophysiology, diagnosis, prevention,
treatment and prognosis of this group of conditions which are generically
described as ischemic cerebral injuries of prematurity and which
may be the result of injuries of a hemorrhagic nature or of damage
to cerebral white matter with ischemic involvement from onset, known
as leukoencephalopathy or PVL ().
Hemorrhagic injury progressing to ischemic brain
The typical case PVIVH is an initially hemorrhagic injury and is
a frequent complication of prematurity. Approximately 26% of very
low birth weight infants between 501 g and 750 g and 12% of those
between 751 g and 1,000 g will develop severe forms of hemorrhage
Initial cerebral hemorrhage in the preterm occurs in the germinal
matrix subependymal, which is a richly vascularized area located
between the caudate nucleus and the thalamus, at the level of Monro's
foramen. The vascular network that feeds the germinal matrix is
very primitive during the early phases of pregnancy. Between 26
and 34 weeks' gestational age the vascular walls are made up only
of endothelium, with no smooth musculature, elastin or collagen
A hemorrhage is defined as intraventricular when it affects the
lateral ventricles and bleeding can occur in the posterior fossa
with resultant arachnoiditis. Post-hemorrhagic ventricular dilatation
is a common complication, probably due to compromised cerebrospinal
fluid reabsorption as a result of obstructed Luschka & Magendie
The most extensive type of PVIVH is parenchymal hemorrhage, involving
the periventricular white matter. As the condition progresses, a
porencephalic cyst may develop at the point where the original hemorrhage
occurred. There is generally just one of these in contrast with
cysts resulting from PVL ().
This is an injury with hemorrhagic origins, but a number of different
studies have found evidence of venous infarction among neuropathological
findings, i.e. the subependymal hematoma causes an obstruction to
venous blood flow and the elevated intraventricular pressure releases
vasoconstrictive substances into the area, both of which conditions
promote cerebral ischemia as a final result ().
The initial lesion is bleeding from the microcirculation into the
germinal matrix with multifactor etiology. The reduced blood flow
through the vessels within the germinal matrix is secondary to parenchymal
hemorrhage, which may take place during intrauterine life or the
postnatal period. The increase in venous pressure is also an important
intravascular hemorrhage mechanism. In ailing newborns, cerebral
circulation is pressure-passive, i.e. cerebral blood flow (CBF)
is directly dependent upon systemic arterial pressure. The premature
brain exhibits a vascular border zone in the germinal matrix, which
is an area that is extremely vulnerable to damage when there is
a drop in cerebral perfusion pressure ().
There are clinical associations between fluctuations in systemic
arterial pressure and CBF velocity in preterm newborns with HMD
and mechanical ventilation with PVIVH. Rapid volume expansion or
the existence of associated complications such as pneumothorax and
interstitial emphysema promote increased CBF and consequently PVIVH
Clinical findings are not specific to cerebral hemorrhage. Muscular
spasms, characteristic leg movements ("pedaling"), convulsive
crises, apnea, pallor and peripheral perfusion deficit are all common.
A sudden drop in hematocrit and hemoglobin in association with an
oversized, tense or bulging bregmatic fontanelle is highly predictive
of PVIVH. Clinical PVIVH usually takes place during the first 72
hours of postnatal life or by the end of the first week. The characteristic
clinical history is of a premature newborn, with respiratory insufficiency
(HMD and/or congenital pneumonia ), requiring mechanical ventilation,
presenting systemic hypotension, pallor, no response to stimuli,
in semi-coma or full coma or convulsive crisis with definite etiology
related to metabolic problems and cerebral hypoxia. Peripheral perfusion
deficits are common, reminiscent of septic shock. Metabolic acidosis
and pulmonary hemorrhage are common findings.
Injuries that are initially hemorrhagic can be asymptomatic. Intracranial
hemorrhage, diagnosed by transfontanellar ultrasound screening at
3 to 5 days of postnatal life, furnishes a diagnosis in 80% of newborn
babies, many of whom are asymptomatic (more than 70% of cases are
diagnosed by ultrasound alone). Nevertheless, newborn babies with
severe PVIVH will often present symptoms and the hemorrhage has
an earlier onset, often within the first 24 hours of life, with
convulsive crises being the most frequently observed clinical presentation
Convulsions secondary to PVIVH are a sign of poor prognosis and
are generally associated with severe cases of cerebral hemorrhage,
with parenchymal complications or periventricular hemorrhagic infarction.
They take place during the first 3 days of life, in very sick extreme
preterms. Clinically they are tonic and generalized with a poor
electroencephalogram (EEG) and dissociation between clinical and
electroencephalographic findings. During the acute phase patients
can progress to coma and death.
Cerebral ultrasound (US)
This is the test of choice for diagnosis. It should be performed
for all newborn babies whose birth weights are below 1,500 g, in
the first instance at 3 to 5 days of life and then weekly until
hospital discharge, irrespective of the presence of symptoms. The
US scan is performed via the anterior or bregmatic fontanelle,
preferably with a 7.5 MHz transducer for routine scans and a 10-MHz
transducer when a less common lesion is suspected. Images are recorded
on video and can also be printed ().
Serial US scans, after diagnosis, are important for monitoring the
cerebral injuries and to define the extent of the hemorrhage and
any post-hemorrhagic ventricular dilatation. This last is a serious
condition requiring systematic monitoring in order to establish
whether the dilatation is transitory, static or progressive ().
Cerebral ultrasound findings made possible an extremely simple
method for classifying cerebral hemorrhage that is still used today
- Minor hemorrhage: degrees I and II
_Degree I = hemorrhage
located in the germinal matrix only.
_Degree II = intraventricular
hemorrhage, but with normal sized ventricles.
- Moderate hemorrhage: degree III
_Degree III = intraventricular
hemorrhage with acute ventricular dilatation.
- Severe hemorrhage: degree IV
_Degree IV = intraventricular
hemorrhage with cerebral parenchyma involvement.
Despite technological advances in imaging methods such as computerized
tomography (CT) of the encephalon and cerebral nuclear magnetic
resonance (NMR), the test most utilized for diagnosing cerebral
lesions in preterm infants is transfontanellar ultrasound due to
the ease with which it can be performed at the bedside with no need
to transport the patient to radiology, because of the lower cost
of the apparatus and because of the specificity of diagnosis when
compared with NMR ().
Nowadays it is possible to relate certain definitions of lesions
that can be detected via US , with great utility for differential
- Hemorrhage of the germinal matrix and the intraventricular
region without complications: this is a hemorrhage within the germinal
layer or lateral ventricles, including subependymal pseudocyst,
but without periventricular involvement, ventricular dilatation
with cerebrospinal fluid in the spaces, parenchymal hemorrhagic
infarction or loss of cerebral tissue.
- Subependymal pseudocyst: this is a cystic degeneration close
to a hemorrhagic germinal layer, with no cystic abnormalities in
the adjacent cerebral parenchyma.
- Parenchymal hemorrhagic infarction: this is seen as an image
with greatly increased echodensity close to the cerebral parenchyma
in the form of a "V", which extends to the ventricular
margin, associated with hemorrhage in the germinal matrix and the
- Periventricular involvement: identified by the abnormally
elevated echodensity in the region of the periventricular white
matter, with no hemorrhage in the germinal matrix and the ipsilateral
- Cystic PVL: is a cystic lesion adjacent to the periventricular
white matter, which is not preceded by parenchymal hemorrhagic infarction
in the affected region. This type of injury will be dealt with in
detail later in the review.
- Ventricular dilatation: this is dilatation of the lateral
ventricle with such a large volume of cerebrospinal fluid that the
depth of the frontal horn immediately anterior of the caudate nucleus
is more than 3 mm (percentile 97).
- Post-hemorrhagic hydrocephalus: this is the result of an
accentuated increase in pressure due to dilatation of the lateral
ventricle, with excessive cerebrospinal fluid volume reaching a
width of 5 mm or more (above the 97th percentile ).
- Loss of cerebral tissue: easily observed on US . Reductions
in cerebral tissue can be as a result of cystic PVL, parenchymal
hemorrhagic infarction due to a porencephalic cyst or irregular
widening of the lateral ventricles. Generalized cerebral atrophy
can also be observed.
Preventative strategies involve prenatal and perinatal care aimed
at reducing premature birth rates and therefore afford survival
with quality. Early postnatal screening of the most vulnerable population
- preterm babies of very low weight - for cerebral injuries is of
fundamental importance ().
During the prenatal period, it is important to assure the adequate
management of high risk pregnancies, such as when the expectant
mother presents with diabetes, previous arterial hypertension and
hypertensive disease specific to pregnancy, nephropathies of diverse
etiologies, rheumatic disease and uterine malformation, among other
serious situations that require specialized prenatal care and clinical
and laboratory-based monitoring ().
The hypertensive disorders of pregnancy (HDP) or maternal preeclampsia
are related to a reduced incidence of PVIVH, compared with the incidence
found among the children of mothers without HDP (8.2 versus 14%),
probably due to antenatal magnesium sulphate use, which could accelerate
cerebral maturation ().
These results are controversial, to the extent that some authors
associate the administration of tocolytic agents in general, including
magnesium sulphate, with an increased risk of cerebral hemorrhage
The type of delivery is an important part of the pathogenesis of
hemorrhage. Studies have found evidence of increased PVIVH risk
when there is active labor, suggesting that vaginal delivery is
of higher risk than caesarian. However, when confounding variables
are controlled, the role of placental inflammation, in particular
fetal vasculitis, assumes its true importance to the genesis of
The pharmacological agents that have been most studied with respect
of prenatal prevention are: intravenous vitamin K, phenobarbital
and corticoids (betamethasone). Results are controversial even though
many different publications have evaluated the risks and benefits
of administering these drugs to mothers ().
No advantages have been demonstrated in terms of reducing the incidence
of neonatal hemorrhagic injuries from prenatal vitamin K and phenobarbital
administration. In a multicenter study of 600 pregnancies resulting
in premature births from 24 to 33 weeks, there were no differences
in PVIVH incidence between placebo and phenobarbital groups. It
is of interest that 58 and 59% of the mothers in the two groups
were given prepartum betamethasone, demonstrating the beneficial
effect of antenatal corticoid ().
The antenatal administration of intravenous corticoid appears to
be effective. A single dose of betamethasone was effective for reducing
the incidence of PVIVH ().
Prenatal corticoid therapy is related with a reduction in severe
PVIVH because it accelerates the maturation of the germinal matrix
region, increases systemic arterial pressure with improved cerebral
perfusion and appears to be related with less severe cases of HMD
A single course of corticoid is recommended for all pregnancies
that have run from 24 and 34 weeks and are at risk of birth within
24 hours, because it reduces the incidence of HMD, of cerebral hemorrhage
and neonatal mortality ().
Post-natal preventative measures have been much studied, primarily
the administration of phenobarbital, indomethacin and vitamin E,
without compensating results, with the exception of intravenous
Postnatal phenobarbital use was not effective for reducing PVIVH.
Intravenous indomethacin has been used prophylactically during
the first 24 hours of life of preterm very low weight infants, preferentially
between 6 and 12 hours of life, reducing the incidence of severe
PVIVH (degrees III and IV), in addition to its effect closing symptomatic
ductus arteriosus. The neuroprotective effects are the result of
an inhibition of the production of free radicals by the injured
endothelium of the germinal matrix and an acceleration of the vascular
maturation in the germinal matrix region. In animal models, indomethacin
has been demonstrated to modulate changes in CBF in response to
hypercarbic aggression, with reduced serum levels of prostaglandins
and maturation of the germinal matrix microvasculature ().
When these babies are followed-up, the benefits of indomethacin
are not well established, with no observed reduction in the incidence
of CP or other neuromotor sequelae among patients treated prophylactically
Its use is particularly indicated for preterms on mechanical ventilation
whose birth weights are less than 1,250 g ().
Clinical management of PVIVH includes the life support measures
employed for all very low weight preterms with early respiratory
difficulties and/or respiratory insufficiency, on mechanical ventilatory
support, and at high risk of severe cerebral hemorrhage. Careful
monitoring, together with supportive measures, will avoid the area
of hemorrhage increasing in size. Maintaining cerebral perfusion
stable, taking care to maintain normal circulatory volume and systemic
arterial pressure is essential ().
The main life support measures are: maintenance of oxygenation
and perfusion, homeostasis of body temperature, metabolic balance
(glucose), hydroelectrolytic balance (primarily of ions of calcium,
sodium and potassium) and acid-base equilibrium, in addition to
early parenteral nutrition and treatment for convulsions, when present
Maintenance of adequate oxygenation and ventilation
This means maintaining PaO2 levels in the range 50-70 mmHg and
PaCO2 between 35 and 50 mmHg. Hyperoxia can promote reductions in
CBF or potentialize injuries caused by free radicals. The use of
xanthines (aminophylline and derivatives) can reduce CBF and is
not recommended for initial treatment of apnea in asphyxiated preterm
neonates. Hyperventilation is also contraindicated since excessive
hypocapnia (CO2 < 25 mmHg) can reduce CBF.
It is important to maintain cerebral perfusion pressure (CPP),
which is the difference between mean systemic arterial pressure
(MAP) and intra-cerebral pressure (ICP). In other words CPP = MAP
-ICP. Loss of cerebral-vascular auto-regulation means that CPP becomes
a direct reflection of MAP and in order to maintain CPP a minimum
MAP is required of 45-50 mmHg. The use of volume expanders and blood
products should be criteria-based. It is important to avoid large
variations in arterial and venous pressures. Judicious use of invasive
procedures and the minimum possible handling of the infant help
to avoid pneumothorax and pulmonary hypertension, which are situations
in which there is a greater need for positive pressure ventilation
and an imminent risk of severe cerebral hemorrhage for extreme preterms.
Maintaining body temperature within normal limits (36.5-37.2 °C)
is a basic life support measure. At birth it is common for extreme
preterms to maintain a temperature of less than 35 °C for hours,
even with the incubator set to maximum temperature.
Glycemia should be maintained at natural levels, i.e., 75-100 mg/dl.
Hyperglycemia is as prejudicial to extreme preterms as hypoglycemia
is. Test strips are a practical and effective method for monitoring
Hydroelectrolytic and acid-base balance
One should be alert to the maintenance of hydroelectrolytic and
acid-base equilibrium. Nonoliguric hyperkalemia during the first
72 hours of life is common in very low birth weight infants due
to inadequate sodium-potassium cellular pump function. Excessive
urinary losses of sodium and of bicarbonate cause hyponatremia and
metabolic acidosis in preterms with birth weights less than 1,250
Early parenteral nutrition
Adequate nutrition is critical for cerebral development. The dry
weight of the human brain is predominantly composed of lipids and
25% of the white matter is made up of arachidonic acid and docohexaenoic
acid, which are essential to the growth, functioning and integrity
of the brain. A deficiency of essential fatty acids during the initial
development of the brain is associated with hypomyelinization and
cognitive and motor retardation. Neurodevelopmental abnormalities
can be more accentuated in the presence of deficiencies of micronutrients
such as zinc. Intolerance of enteral feeding makes preterms' development
problematic when early parenteral nutrition is not introduced with
an adequate supply of amino acids ().
The drug of choice is intravenous phenobarbital, administered at
20 mg/kg in bolus over a 15 to 20 minute infusion period. A further
dose of 20 mg/kg in bolus may be necessary if crises persist, making
a total dose of 40 mg/kg of phenobarbital, before other anticonvulsive
drugs are associated to control the crisis. A maintenance dose of
phenobarbital (3-5 mg/kg/day; every 12 hours) should be given 12
hours after the initial control dose ().
Long term follow-up studies of very low birth weight preterm infants
continued until academic ages have found evidence of neurobehavioral
problems when CP is not present in 30 to 50% of cases and, of these,
25 to 30% exhibit psychiatric disorders in adolescence, including
schizophrenia, autism, hyperactivity and attention deficit ().
The prognosis of newborn babies with cerebral hemorrhage depends
upon the severity and size of brain damage, in addition to the presence
of complications. When the hemorrhage is degree I or II with no
complications, prognosis is equivalent to that for any other preterm
born at the same gestational age and weight. In other words, educational,
cognitive and motor difficulties will be comparable ().
Gestational age is an independent risk factor for the development
of ischemic and hemorrhagic injuries ().
In a study of a cohort of 852 premature babies born at less than
33 weeks' gestational age, hemorrhagic injuries were directly related
to lower birth weight and gestational age because of physiological
and maturity-related changes to the vascular system, in particular
the germinal matrix, which has already been covered earlier in the
present review ().
Vollmer et al. assessed the efficacy of ultrasound for detecting
brain damage in newborn babies with less than 33 weeks' gestation,
aiming to define the role of these findings in neurodevelopment
at 8 years of age. The authors found that, for premature babies
born at 24 to 32 weeks' gestational age, unfavorable outcomes, with
delayed neuropsychomotor development were dependent on the existence
and type of injury seen by US ().
Preterm babies who had both hemorrhagic and periventricular white
matter injuries, as the years pass, can present certain cognitive
and learning difficulties in addition to varying levels of motor
deficit. This combination is relatively common since the two share
perinatal risk factors ().
Newborn babies who suffer localized, unilateral PVIVH can develop
spastic hemiparesis , involving upper and lower limbs and mild cognitive
retardation. Quadriparesis and significant cognitive deficit are
observed after extensive and bilateral cerebral hemorrhage or when
there is PVL in association ().
A number of studies have shown NMR to be superior to US for the
detection, classification and prognosis of injuries that are initially
hemorrhagic, progressing to ischemic injury, and also for periventricular
white matter damage associated with cerebral hemorrhage ().
The major limitation of NMR is the need to take the patient to the
equipment and the elevated costs.
The complication that most determines the neurological morbidities
observed in the prognosis of preterms of less than 1,500g who have
suffered an initially hemorrhagic injury progressing to ischemic
damage is post-hemorrhagic hydrocephalus ().
Ischemic brain damage
Periventricular leukomalacia consists of an ischemic infarction
in the region of the cerebral white matter adjacent to the lateral
ventricles and is a common occurrence among premature infants born
after less than 35 weeks' gestation. Diagnosis is made by US , which
will initially show a periventricular area of increased echogenicity,
with subsequent development of cystic lesions representing necrotic
This is the classical concept that has been employed until recently
to describe the neuropathological findings from a study by Banker
& Larroche ().
Nowadays, as image-based diagnosis methods have developed it is
possible to observe a new conceptual pattern, cerebral leukoencephalopathy
Findings from NMR scans of very low weight premature babies have
found evidence of an elevated incidence of diffuse white matter
damage, which is even more frequent than cystic PVL. Maalouf et
al. followed 32 preterm newborn babies until 40 weeks' postconceptional
age, when NMR was performed and diffuse brain damage was found in
79% of the patients ().
The term cerebral leukoencephalopathy includes cystic PVL together
with the diffuse white matter injury component and should be used
as a synonym of PVL ().
Focal periventricular necrosis is distributed at the level of the
occipital radiation, at the trigon of the lateral ventricles, and
at the level of the cerebral white matter, around the Monro foramen.
Microscopic changes are the result of coagulation necrosis, with
microglial infiltration, astrocytic proliferation and eventual cystic
formation. Cysts are diagnosed by US when larger than 0.5 cm in
diameter. Cystic cavities reduce in size over time as a result of
progressive glucose metabolism. Long term sequelae include loss
of myelin and focal ventricular dilatation in the trigon region
of the lateral ventricles ().
Diffuse necrosis of the periventricular white matter is most frequent
among very small preterm newborns who require prolonged ventilatory
support, and ventricular dilatation, when present, is more preeminent
than with focal necrosis ().
Premature newborns are more susceptible to predominantly ischemic
injuries of the periventricular white matter for three basic reasons
- Cerebral blood flow is reduced more through the white matter
than in other areas of the brain, such as the cerebral cortex.
- Immature oligodendrocytes are more susceptible to damage encouraged
by free radicals and certain cytokines, such as interleukin-6
(IL-6), interleukin-1 (IL-1b) and tumor
necrosis factor alpha (TNF-a), in addition
to the greater potential for toxicity induced by glutamate, when
the brain is less mature.
- A previous history of intrauterine infection has a positive
interaction with ischemic damage, potentializing the risk of white
These three motives will be dealt with in a more detailed manner
later in the review in the section on the pathophysiology of white
Cerebral leukoencephalopathy is the principal ischemic lesion in
extreme preterms, occurring in 7 to 26% of these patients. Clinical
and epidemiological findings indicate that cerebral white matter
damage detected by ultrasound is the primary predictor of CP among
very low birth weight newborns. Newborns with weights of less than
1,500 g and PVL present CP in 62 to 100% of cases ().
The type of ischemic damage to the white matter can define the
problems that will be observed as extreme preterms progress. Diffuse
periventricular white matter damage is related with cognitive and
behavioral deficits, while focal necrotic damage in PVL, with profound
white matter involvement is related to CP ().
Hypoflow and cerebral leukoencephalopathy
The factors that determine cerebral leukoencephalopathy or PVL
have not yet been adequately established. Pathogenesis is complex
and multifactor. The genesis of ischemic brain damage involves vascular
factors that increase the risk of cerebral hypoperfusion and the
intrinsic vulnerability that occurs due to the differentiation of
oligodendroglial cells in the area of the cerebral white matter.
As a result of this, prematurity and insufficient cerebral perfusion
are very important causes of brain damage ().
Systemic hypotension causes an immediate reduction in CBF and,
as a function of the immaturity of cerebral vasculature reactivity,
premature infants' brains suffer from these alterations directly.
A number of different conditions can cause systemic alterations
in premature infants and are possibly involved in the pathogenesis
of PVL ().
Clinically, the reduction in CBF can take place in the preterm in
response to a variety of different conditions : septic shock with
systemic hypotension, persistent apnea, significant acidosis, hypocarbia,
persistent ductus arteriosus and severe congenital heart disease
with low systemic output are examples of conditions associated with
Cerebral vascular bed development depends directly on gestational
age. The shorter vascular branches which have less anastomosis,
resulting in a border zone with insufficient vascularization and
a predisposition to PVL, are more frequent in premature infants
of 24 to 30 weeks' gestational age. From the 32nd week onwards there
is significant development of the cerebral vascular bed, with longer
vascular branchings appearing which have more anastomosis ().
This being so, diffuse white matter injury is related with greater
cerebral immaturity than focal necrotic damage ().
The periventricular white matter vascular bed exhibits a more limited
vasodilatory response than other parts of the brain, with greater
risk of ischemic injury from reduced CBF. During the post-ischemia
reperfusion phase CBF drops and autoregulation is lost, increasing
even further the risk of ischemia in the border zone regions of
the white matter ().
Developing oligodendroglial cells (immature) are particularly susceptible
to hypoxic-ischemic insult and reperfusion. The reduction in CBF
causes anaerobic glycolysis and lactate production and, as a result,
there is metabolic acidemia and increased calcium ions in the intracellular
space. Calcium entering the cell activates the liberation of excitatory
neurotransmitters such as glutamate and aspartate, with the liberation
of free radicals. Ischemia-reperfusion encourages microglia activation,
resulting in the formation of free radicals which lead to cell death,
principally of the pre-oligodendrocyte cells. This pathophysiologic
mechanism is characteristic of diffuse periventricular white matter
damage. In other words, in diffuse injury there is predominantly
a loss of cells from the oligodendroglial lineage ().
Cytokines, proteins with actions similar to hormones, are also
mediators of oligodendroglial cell death. In animal models ischemia-reperfusion
is responsible for rapid microglia activation, cytokine liberation
and resultant migration of a number of different inflammatory cells,
such as monocytes and macrophages ().
Cytokines and cerebral leukoencephalopathy
A number of different perinatal inflammatory and infectious conditions
have been implicated in the pathogenesis of cerebral leukoencephalopathy.
The inflammatory pathway, mediated by cytokines is highly involved
in nervous cell death by neuronal apoptosis ().
In the central nervous system (CNS), microglia can liberate TNF-a,
IL-1b and IL-6, inducing reactive astrocytosis.
The toxicity of TNF-a in inducing apoptosis
has been demonstrated with cultures of oligodendroglial cells ().
Tumor necrosis factor alpha appears to be a mediator of acute inflammatory
response that regulates the secretion of IL-1b,
exhibiting effects in synergy with that cytokine. Tumor necrosis
factor alpha stimulates the production of IL-1b
by monocytes, and is pyrogenic in the same way that IL-1b
Elevated levels of IL-1 can be related to disease severity if they
are accompanied by elevated TNF-a levels
A diagnosis of fetal inflammatory response syndrome can be made
by cytokine assay from umbilical cord blood, by means of cordocentesis.
There is a causal interrelationship between ascendant intrauterine
infection, with local cytokine production and premature labor. The
proinflammatory cytokines most described in intrauterine infections
are: TNF-a, IL-1b,
IL-6 and IL-8. Interleukin 6 is the best known mediator of acute
inflammatory response, liberated quickly after a bacterial invasion.
It is secreted by monocytes, macrophages, endothelial cells and
fibroblasts in response to other inflammatory mediators such as
TNF-a and IL-1b().
Interleukin 6 is also synthesized within the neurons and neuroglia
and its expression is elevated in a large variety of CNS disorders,
presenting neuroprotective and neurotrophic effects ().
A number of different studies describe elevated IL-6 in cord blood
in the presence of funiculitis and chorioamnionitis, showing that
IL-6 assay in amniotic fluid is a sensitive and specific method
for identifying microbial invasion of the amniotic cavity, although
it is an invasive method and the ideal test would be safer, but
deliver the same efficacy ().
Jong et al. assessed IL-6 levels at the uterine cervix of patients
with premature membrane rupture, comparing them with IL-6 levels
in amniotic fluid and concluded that IL-6 assays from cervical secretions
have an excellent diagnostic value for bacterial invasion of the
amniotic cavity and prognostic value for infectious complications
during the neonatal period, although this last was only identifiable
at extremely high IL-6 levels above 350 pg/ml ().
Measurements of IL-6 at the uterine cervix can reduce the need for
amniocentesis, which is routinely performed at the majority of services
to identify maternal infections.
In a case-control study IL-1-b, TNF-a
and IL-6 were assayed by immunohistochemistry with significantly
more elevated levels being observed among newborn babies who had
had PVL listed in autopsy findings, when compared with those whose
brains were normal on autopsy ().
These cytokines induce the expression of adhesion molecules, such
as the vascular cell adhesion molecule (VCAM-1), within the CNS,
both in the parenchyma and the vascular endothelium, and can compromise
microglia activation and lead to demyelination ().
Summing up, the pathophysiologic events of cerebral leukoencephalopathy
are centered on two primary aspects: 1) The reduction of cerebral
perfusion in very small preterms with deficient cerebral-vascular
auto-regulation and a high risk for periventricular white matter
injury 2) Preterm newborn babies exposed to intrauterine infection
are vulnerable to pre-oligodendrocyte cell death in the face of
ischemic insult, even if mild, which would not be sufficient to
The diagnosis of ischemic brain injuries involves the determination
of factors associated with cystic PVL ().
In cystic PVL, the presence of cysts can be observed from birth
onwards due to the occurrence of an intrauterine injury, or appear
after birth, generally at 2 to 3 weeks of life. The perinatal events
which can cause intrauterine injuries are: clinical or subclinical
maternal chorioamnionitis (microscopic diagnosis), premature rupture
of amniotic membranes, funiculitis, and other maternal infectious
conditions during the peripartum period ().
Neonatal factors frequently associated with a diagnosis of leukoencephalopathy
are: perinatal asphyxia, hypovolemia, sepsis, hypocarbia, symptomatic
patent ductus arteriosus and recurrent apnea with bradycardia. Many
of these factors cause a reduction in systemic blood pressure. Immaturity
is most important factor for diagnostic suspicion and, the greater
the complications during the preterm's hospital stay, the greater
the chances of leukoencephalopathy. It is often not possible to
establish whether leukoencephalopathy is the cause of unfavorable
neonatal outcomes or a consequence of the innumerable intercurrent
clinical conditions that are common during this period ().
Early diagnosis of white matter injuries, in common with injuries
that begin as hemorrhagic and progress to ischemia, is obtained
by US because, in the majority of cases, presentation is subclinical
Ultrasound is a rapid test, easy to perform, that can be realized
without taking the patient to the Radiology Service, using a 7.5
MHz high-frequency transducer. Serial US scans should be taken until
term (40 weeks' postconceptional age) in order to identify cases
that could develop cystic PVL during the first month of life ().
The protocol employed is 1 or 2 scans during the first week of life,
indicated from the 3rd day of life onwards. Further ultrasound control
scans should be performed at around days 10, 14, 21 and 28. For
babies born at gestational ages of less than 30 weeks an additional
scan is required at approximately 45 days of life ().
If any abnormality is observed on US , scans should be repeated
weekly, or even more frequently, if clinically indicated ().
Cerebral white matter injury is defined as at least one of the following
echographic findings ():
- The presence of cystic lesions of at least 0.5 cm in diameter.
These are distributed bilaterally and located close to the external
angles of the lateral ventricles.
- Image of diffuse echodensity persisting for a period of more
than 14 days, without cystic formations.
- Unilateral parenchymal hyperdensity or unilateral porencephalic
cyst, probably caused by ischemic and hemorrhagic infarction. There
will be periventricular hemorrhagic parenchymal involvement, compromising
the germinal matrix layer.
Ventricular dilatation without cerebral hemorrhage
Nuclear magnetic resonance is an expensive test and should be reserved
for special cases. It is indicated for premature infants whose gestational
ages were less than 30 weeks at birth at the point of their hospital
discharge. The finding that is characteristic of PVL is a diffused,
excessively high intensity signal located in the region of the white
Magnetic resonance imaging by diffusion is an NMR technique that
measures the movement of the liquid part of cerebral tissue, making
it possible to detect white matter abnormalities in the brains of
preterms before conventional NMR. A normal result on this test reveals
a reduction in the measurement of the liquid in the cerebral white
matter of preterms when corrected age approaches term (40 weeks'
postconceptional age) ().
Currently, the preventative measure which has the greatest impact
is the adoption of strategies aimed at adequate prenatal care aimed
at reducing the rates of premature births. Infectious intrauterine
conditions are present in more than 25% of premature births and
prematurity is highly associated with the occurrence of CP ().
The administration of antibiotic therapy to mothers in premature
labor can bring indirect benefits, reducing the fetal inflammatory
response and thereby diminishing the chance of PVL.
Preventative measures adopted during the neonatal period are not
easily implanted because they involve all of the neonatal care offered
to premature newborns, since the pathophysiology is complex, multifactor
and remains ill-defined and also because newborn babies are frequently
asymptomatic, with diagnosis established by neuroimaging methods
It is of fundamental importance to perform ultrasound and magnetic
resonance imaging as screening tests at suitable points, in order
to prevent or minimize sequelae with the employment of a multidisciplinary
approach as early as possible.
The prevention of small ischemic insults, especially in newborn
babies exposed to maternal intrauterine infection, such as chorioamnionitis,
includes agents that reduce the production of free radicals, antioxidants,
other components that clear free radicals, glutamate antagonists
and agents that prevent microglial activation of infection products
The principal life support measures are the same as those employed
for PVIVH, i.e. the maintenance of tissue oxygenation and perfusion,
homeostasis of body temperature, metabolic balance (glucose), hydroelectrolytic
balance and acid-base equilibrium, early parenteral nutrition and
treatment for convulsions, when present ().
Strategies that are more specific to cerebral leukoencephalopathy
- Suitable treatment for children with blood pressure low for
their age, with rapid volume expansion and/or inotropic support,
depending on clinical condition and arterial pressure ().
- Judicious use of mechanical ventilation for lung diseases,
avoiding hypocarbia caused by inappropriate ventilation techniques.
Hypocarbia induced by mechanical ventilation is associated with
increased average airway pressure, which provokes a fall in venous
return and cardiac output, increasing pressure at the sagittal
sinus. The increase in venous pressure and reduction in CBF provoked
by hypocarbia result in a reduction in cerebral perfusion pressure,
including of the periventricular white matter ().
- Treatment of apnea with bradycardia. Xanthines are indicated
to treat apnea of prematurity and, in some cases ventilatory support
may be necessary ().
Wu & Colford, in a meta-analysis (19 studies), found a significant
association between clinical maternal chorioamnionitis and CP and
cystic PVL in preterms. Microscopic chorioamnionitis (seven studies)
was significantly associated with the development of cystic PVL
Microscopic chorioamnionitis has been identified as a risk factor
for CP among very low birth weight infants.54,56 Observed levels
of IL-6, IL-8, TNF-a and IL-1b
are elevated in the cord blood of newborn babies who later develop
PVL and CP ().
These cytokines may possibly be useful in the future as early markers
of neurological prognosis.
The most common sequela of cystic PVL is spastic diplegia. Diffuse
white matter injuries exhibit wider involvement, with spastic quadriplegia,
in addition to cognitive and behavioral deficits ().
The cause of the cognitive deficits has not yet been identified.
It is possible that the white matter damage alters the organization
of cortical neurons, causing damage to the subplate neurons ().
Prognosis is greatly dependent on maternal infectious history,
on the time of diagnosis, type of injury, whether diffuse or focal,
and also on the preventative and therapeutic measured employed during
the perinatal and postnatal periods.
The disease is new, since it is the consequence of the survival
of ever more immature babies and of improved neuroimaging methods,
making diagnoses more precise. There is a need for more in-depth
clinical studies which provide a basis for preventative and therapeutic
strategies, in order to improve the prognosis of these extremely
preterm newborn babies, which is the population most vulnerable
to these insults.