Abstract
This chapter focuses on a brief review of the pathogenesis of periventricular intraventricular hemorrhage as well as white matter injury. Various approaches or strategies for the prevention, diagnosis, and treatment as well as outcomes are discussed with gaps in knowledge highlighted.
Keywords
antenatal steroids, indomethacin, intraventricular hemorrhage, periventricular leukomalacia
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Periventricular-intraventricular hemorrhage
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Periventricular white matter injury associated with IVH
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White matter injury in the absence of hemorrhage
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Outcome
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Gaps in knowledge
HW was a 700-g 24-week premature twin B male infant born to a 29-year-old G1P0 (gravida 1, para 0) mother whose pregnancy was complicated by the onset of premature labor. The mother received a dose of betamethasone approximately 6 hours before a vaginal delivery. She also received antibiotics and was given magnesium sulfate. The infant was delivered with minimal respiratory effort and a heart rate of 70 beats/min. Resuscitation included bag-mask ventilation with room air and intubation, with a rapid improvement in heart rate. The infant was admitted to the intensive care unit and was given one dose of a surfactant for respiratory distress syndrome (RDS). The early course was complicated by a pneumothorax as well as a pulmonary hemorrhage, with associated hypoxic respiratory failure and significant metabolic acidosis. A head ultrasound scan showed a grade III intraventricular hemorrhage on the left with dilation of the ventricle and an associated ipsilateral intraparenchymal echodensity involving frontoparietal white matter. In addition, the infant developed a hemodynamically significant patent ductus arteriosus (PDA) that was initially treated with indomethacin. The infant was weaned to continuous positive airway pressure by day of life (DOL) 14, and was briefly reintubated for the surgical ligation of the PDA and on the second occasion for a late-onset sepsis. Other issues included recurrent apnea and bradycardia and frequent unprovoked desaturation episodes. He required supplemental oxygen through the 35th week of postmenstrual age. He required parenteral nutrition for 3 weeks and subsequently received enteral breast milk. Serial head ultrasound scans on DOLs 7, 14, 28, 42, and 56 revealed progressive communicating hydrocephalus involving the lateral third and fourth ventricles that peaked in dilation by DOL 28 and then gradually decreased in size by DOL 56. The parenchymal lesion evolved into a small left porencephalic cyst. The infant underwent a magnetic resonance imaging (MRI) evaluation on DOL 92 that revealed mild ventriculomegaly and the left cystic lesion and some periventricular white matter loss. The infant was discharged on DOL 100. He was seen and evaluated at 18 months. At that time the clinical findings indicated mild right hemiparesis. He recently started walking, was very active, and had minimal speech. Evaluation using the Bayley Scales of Infant and Toddler Development (BSID) found that he had a cognitive score of 75 and a motor score of 82.
This case illustrates a typical course of an extremely premature infant who is at greatest risk for severe periventricular-intraventricular hemorrhage (PV-IVH) even when managed in the current era of neonatology. Although the overall incidence of PV-IVH in the premature infant has decreased, hemorrhage remains an important problem in the extremely low-birth-weight infant (ELBW, birth weight <1000 g), particularly in cases of rapid delivery when the potential for full dosing of glucocorticoids around the time of delivery is not possible. This chapter focuses on a brief review of the pathogenesis of PV-IVH as well as white matter injury. Various approaches or strategies for the prevention, diagnosis, and treatment as well as outcomes are discussed, with gaps in knowledge highlighted.
Periventricular-Intraventricular Hemorrhage
Background
The overall occurrence of PV-IVH has declined with time, although severe intraventricular hemorrhage remains a significant clinical problem in the ELBW population. For those born at or before 28 weeks’ gestation, 15% still have the most severe forms of hemorrhage, occurring in 37% of those born at 23 weeks and 24% in infants born at 24 weeks. This observation is highly relevant because survival of the infants born at the limits of viability continues to increase, and long-term neurocognitive deficits are more likely with severe hemorrhage. However, evidence also points to neurodevelopmental deficits even with lesser grades of hemorrhage and even when the cranial sonogram is interpreted as being normal (see later discussion). These observations are important because they point to the limitations of cranial sonography in identifying more subtle injury to the cortex, deep gray matter, or cerebellum. These are more readily identified by MRI studies performed closer to term.
Neuropathology: Relevance to Clinical Findings
The primary lesion in PV-IVH is bleeding from small vessels in the subependymal germinal matrix (GM), a transitional gelatinous region that provides limited support for the luxurious but very immature capillary bed that courses through it. With maturation, this matrix region becomes less prominent and is essentially absent by term gestation. The hemorrhage, when it evolves, may be confined to the GM region (grade I IVH), or it may extend and rupture into the adjacent ventricular system (grade II or III IVH, depending on the extent of hemorrhage), or extend into the white matter (termed a grade IV or intraparenchymal echogenicity [IPE]) ( Fig. 2.1A ). IPE, which is invariably unilateral, represents an area of hemorrhagic necrosis of varying size within periventricular white matter, dorsal and lateral to the external angle of the lateral ventricle ( Fig. 2.1B ).
Pathogenesis
The genesis of bleeding from capillaries within the GM is complex and includes a combination of intravascular, vascular, and extravascular influences. Intravascular factors, especially those that involve perturbations in cerebral blood flow (CBF), have a critical role in capillary rupture and hemorrhage. Thus it has been shown, through the use of different methods to assess CBF, including Doppler ultrasonography, near-infrared spectroscopy, and xenon-enhanced computed tomography (CT), that the cerebral circulation of the sick infant is pressure passive—that is, CBF varies directly with changes in systemic blood pressure. This state would be expected to increase the vulnerability of the GM capillaries to periods of both hypotension and hypertension, and this is supported in experimental studies and clinical observations. In a beagle puppy model, GM hemorrhage can be produced by systemic hypertension with or without prior hypotension. In addition, clinical temporal associations have been demonstrated between fluctuations in systemic blood pressure and simultaneous fluctuations in CBF velocity as may occur in the ventilated premature infant with RDS, increases in CBF as may occur with rapid volume expansion or a pneumothorax, and the subsequent development of PV-IVH. Conversely, decreases in CBF secondary to systemic hypotension, which may occur in utero or postnatally, may also play a prominent role in the genesis of PV-IVH in certain infants. Hypercarbia produced by potential modulation of autoregulation increases the risk for severe IVH. A presumed mechanism in this context is that of rupture upon reperfusion. Finally, elevations in venous pressure may be an important additional intravascular mechanism of hemorrhage and may reflect the peculiarity of the anatomy of the venous drainage of GM and the white matter. Thus at the level of the head of the caudate nucleus and the foramen of Monro, the terminal, choroidal, and thalamostriate veins course anteriorly to a point of confluence to form the internal cerebral vein. The blood flow then makes a U -turn at the usual site of hemorrhage, raising the possibility that an elevation in venous pressure increases the potential for venous distention with obstruction of the terminal and medullary veins and hemorrhagic infarction. Indeed, simultaneous increases in venous pressure have been observed in infants who exhibit variability in arterial blood pressure, such as when it occurs with RDS and associated complications, such as pneumothorax and pulmonary interstitial emphysema, or with mechanical or high-frequency ventilation. To summarize, it is likely that both arterial and venous perturbations contribute to the genesis of IVH. Later evidence suggests that these intravascular responses may be modulated by inflammation or the administration of medications to the mother, such as glucocorticoids (see later discussion). In one series, infants with fetal inflammation had a significantly higher incidence of severe IVH than infants with no fetal inflammation (49% vs. 17%) ( P = .04). Infants with fetal inflammation had a significantly higher heart rate ( P = .005), catecholamine index ( P = .02), and volume load ( P = .02) in the first 24 hours of life.
In addition to the intravascular factors, vascular and extravascular influences—the poorly supported blood vessels, excessive fibrinolytic activity noted within the matrix region, and a prominent postnatal decrease in extravascular tissue pressure—may all contribute to hemorrhage.
Periventricular White Matter Injury Associated With IVH
The pathogenesis of white matter injury associated with hemorrhage remains unclear but appears to be closely linked to the adjacent bleed. Two potential pathways have been proposed to explain this intricate relationship. The first suggests a direct relationship to the PV-IVH, on the basis of several clinical observations, as follows: (1) the white matter lesion is always noted concurrent with or following a large GM and/or IVH and is rarely if ever observed before the hemorrhage; and (2) the white matter injury is always observed ipsilateral to the side of the larger hemorrhage when there is bilateral involvement of the ventricular system. This consistent relationship between the GM and the white matter injury may in part be explained by the venous drainage of the deep white matter (see earlier discussion). A second explanation is a de novo evolution of white matter injury. Thus it is proposed that the PV-IVH and the white matter injury occur concurrently. Because both the GM and the periventricular white matter are border-zone regions, the risk for ischemic injury is increased during periods of systemic hypotension, particularly in the presence of a pressure-passive cerebral circulation. Hemorrhage in these regions may then occur as a secondary phenomenon, or reperfusion injury. In support of this theory is the fairly consistent observation of the simultaneous detection of PV-IVH and white matter injury on cranial ultrasonography. Moreover, elevated hypoxanthine and uric acid levels (as markers of reperfusion injury) have been observed on the first postnatal day in infants in whom white matter injury subsequently developed.
Identification of the mechanisms contributing to periventricular white matter injury is crucial to prevention of this lesion. If the white matter injury is directly related to PV-IVH, then prevention of the latter should reduce the occurrence of the white matter injury. However, if the PV-IVH and the white matter injury occur simultaneously as a result of a primary ischemic event with the hemorrhage occurring as a secondary phenomenon, then prevention of the secondary hemorrhage may not affect the primary ischemic lesion. Indeed, the two follow-up studies on indomethacin treatment to prevent IVH in the neonatal period are supportive of this latter concern. Thus, although the incidence of severe IVH was reduced in infants treated with indomethacin in both studies, neurodevelopmental outcomes at 18-month follow-up, including cerebral palsy, were comparable in the indomethacin-treated group controls.
Clinical Features
In most cases (up to 70% of less severe IVH cases), the diagnosis is made with a screening sonogram. In the earlier descriptions of PV-IVH, the majority of cases, about 90%, evolved within the first 72 hours of postnatal life. However, the time to initial diagnosis of hemorrhage has shifted to a later onset in recent years. Thus for neonates weighing less than 1000 g, the IVH diagnosis is made early, within the first 24 hours in approximately 80% of infants. However, some cases are now noted after the 10th postnatal day. This changing pattern may reflect the complexity of disease in the tiniest infants and the extent of supportive medical care, especially the prolonged use of high-frequency ventilation. Infants with the more severe IVH frequently exhibit clinical signs such as a bulging fontanel, seizures, a drop in hematocrit, hyperglycemia, metabolic acidosis, and pulmonary hemorrhage.
Complications
The two most significant complications of IVH are extension into adjacent white matter (see earlier discussion) and the development of posthemorrhagic hydrocephalus.
Prevention
Perinatal Strategies
Antenatal Steroids
Various perinatal and postnatal strategies have been investigated for the prevention of PV-IVH. The antenatal administration of glucocorticoids to augment pulmonary maturation has had the positive, unanticipated benefit of a significant reduction in the incidence of IVH and severe IVH. A systematic review of 26 trials showed antenatal corticosteroid therapy to be associated with a reduction in the occurrence of PV-IVH (relative risk [RR] 0.54, 95% confidence interval [CI] 0.43–0.69; 13 studies, 2872 infants), and severe hemorrhage (RR 0.28, 95% CI 0.16–0.5; 5 studies, 572 infants). The mechanisms whereby glucocorticoids reduce severe IVH remain unclear but may relate to less severe RDS, possibly minimizing fluctuation in cerebral blood flow and accelerated stabilization of the germinal matrix vasculature by modulating vascular growth factors. Serial courses of antenatal corticosteroids are not recommended; a single rescue course is to be considered if preterm birth does not occur within a week to further decrease the risk of RDS but has no further impact on the rate of IVH or severe IVH. There are concerns that multiple courses of antenatal corticosteroids may have adverse effects on the developing brain. Thus infants who were exposed to multiple courses (median of 4) of antenatal steroids had a higher incidence of cerebral palsy than a placebo group, although the difference was not statistically significant (6/206 vs. 1/195; P = .12).
Pregnancy-Induced Hypertension
One maternal medical condition associated with a lower incidence of IVH is pregnancy-induced hypertension (PIH). In one report a lower incidence of severe PV-IVH was found in infants born to mothers with PIH (8.2%) than to those without PIH (14%), with an odds ratio (OR) estimate of 0.43 (95% CI 0.30–0.61), a finding consistent with other reports. The mechanisms through which the risk of IVH may be reduced by the presence of PIH remain unclear, but accelerated brain maturation in such infants is possible.
Magnesium Sulfate
The use of magnesium sulfate in these women was initially suggested to be contributory to the reduction in IVH, but subsequent studies have shown that it is not. Tocolytic agents, in general, including magnesium sulfate, are associated with an increased risk for IVH. However, a large prospective, randomized controlled trial of magnesium sulfate administered to mothers at 24 to 31 weeks’ gestation demonstrated a reduced rate of cerebral palsy among infant survivors. Subsequent randomized controlled trials showed similar neuroprotection. Thus a meta-analysis of antenatal magnesium sulfate therapy given to women at risk for preterm birth concluded that it substantially reduced the risk of cerebral palsy in the child (RR 0.68; 95% CI 0.54–0.87; in 5 trials involving 6145 infants). The number of women needed to be treated to benefit one infant by avoiding cerebral palsy is 63 (95% CI 43–155). The American Congress of Obstetricians and Gynecologists (ACOG) recommends intrapartum magnesium for women at less than 32 weeks’ gestation who are at risk for delivery within 7 days.
Route of Delivery
There are conflicting data regarding the route of delivery and subsequent IVH. Interpretation of the data is difficult because most studies are retrospective, but this does not exclude the possibility that under certain circumstances, intrapartum events may contribute to the pathogenesis of severe IVH. Some studies show a higher risk for IVH with increasing duration of the active phase of labor, and a lower risk in infants delivered via cesarean section before active phase of labor. Many of these studies were analyzed before the more frequent use of antenatal glucocorticoids. In a study in infants born at less than 750 g whose mothers were given steroids, vaginal delivery was a predictor for severe IVH. By contrast, in a retrospective cohort study of ELBW infants, the influence of labor on those born by cesarean delivery was examined and this analysis revealed that labor does not appear to play a significant role in the genesis of IVH. Similarly, in a later retrospective analysis, severe IVH was not influenced by mode of delivery in vertex-presenting, singleton, very LBW infants after data were controlled for gestational age. Any analysis that evaluates the impact of labor or route of delivery must account for an important role of placental inflammation, in particular fetal vasculitis, in the genesis of IVH, a role that may supersede the influence of the route of delivery. Thus in one study, although vaginal delivery was associated with an increased risk of IVH by univariate analysis, the risks attributable to vaginal delivery were no longer increased when adjustments were made in multivariate analysis for fetal vasculitis and other potential confounding factors.
Delayed Cord Clamping
Several randomized controlled trials have shown improved neonatal outcomes, including a decreased rate of IVH, with delayed cord clamping. A meta-analysis showed a reduction of all grades of IVH by ultrasound (RR 0.59, CI 0.41–0.85 in 10 trials involving 539 infants). Other benefits seen include increases in the neonatal hematocrit, the need for fewer blood transfusions, and a lower risk for necrotizing enterocolitis. One study in preterm infants born before 32 weeks showed that delayed cord clamping was protective against low motor scores at 18 to 22 months corrected age. ACOG and the American Academy of Pediatrics (AAP) recommend a delay in cord clamping for vigorous preterm infants for at least 30 to 60 seconds. Proposed mechanisms for the benefits associated with delayed cord clamping include an improved cardiovascular transition. The optimal timing for infants requiring resuscitation is not yet clear, and further studies are currently under investigation to answer gaps in knowledge with this practice.
Postnatal Strategies
Any approach to intervention should at the least consider the following: (1) the target population should be those infants in whom severe IVH is most likely to develop—that is, with birth weights less than 1000 g ; and (2) the condition of the infant at delivery, which appears to be an important mediator of subsequent IVH ( Box 2.1 ). The latter appears to be strongly influenced in part by perinatal events and, in particular, the administration of antenatal glucocorticoids or the presence of fetal vasculitis.
High Risk
Minimal intrapartum care
No glucocorticoid exposure
Chorioamnionitis/funisitis
Fetal distress
Lower gestational age
Lower birth weight
Respiratory distress syndrome
Respiratory morbidity (i.e., pneumothorax)
Fluctuations or rapid elevations in systemic blood pressure and/or cerebral blood flow
Hypotension
Sudden and repeated increases in venous pressure
Lower Risk
Antenatal glucocorticoids (short course)
Medical condition (e.g., pregnancy-induced hypertension)
Intrauterine growth restriction
Higher gestational age
Higher birth weight
Postnatal medications (e.g., indomethacin)
Postnatal Factors Associated With an Increased Risk
Postnatal factors associated with a higher risk for IVH include decreasing gestational age, lower birth weight (<1000 g), male sex, intubation, and RDS (see Box 2.1 ). In contrast, the risk for severe IVH in the nonintubated infant is low(<10%). For infants with RDS, the risk for IVH is even greater with associated perturbations in arterial and venous pressures as well as with hypercarbia. These vascular perturbations are in part related to the infant’s breathing patterns, which are usually out of synchrony with the ventilator breath. The perturbations can be minimized with careful ventilator management, including the use of synchronized mechanical ventilation, assist/control ventilation, sedation, or, in more difficult cases, paralysis. Interestingly enough, although surfactant administration improved respiratory ventilation, the improvement was not accompanied by a significant reduction in the incidence of IVH.
Postnatal Administration of Medications to Reduce Severe IVH
Medications administered postnatally to reduce or prevent IVH have included phenobarbital, vitamin E, ethamsylate, and indomethacin. Although there was initial enthusiasm for the use of each of these medications in the prevention of IVH, the effect has not been borne out over time. In one noteworthy study, infants who received phenobarbital exhibited a higher incidence of severe IVH than controls.
Indomethacin
Currently, the early postnatal administration of indomethacin is believed to be of benefit in the prevention of severe hemorrhage. Two studies demonstrated a significant reduction in the incidence of severe IVH in infants who received indomethacin in comparison with control infants. However, at long-term follow-up, the incidence of cerebral palsy was comparable in the two groups. This observation, coupled with the known reduction in CBF that accompanies indomethacin administration, warrants cautious use of this agent. We administer indomethacin to those infants at greatest risk, such as those delivered precipitously without the benefit of antenatal steroids. Using this approach the overall incidence of severe IVH for infants between 23 5/7 weeks and 28 6/7 weeks was 5.5% for the years 2010–2015. ( Fig. 2.2 ).
White Matter Injury in the Absence of Hemorrhage
BS was a 28-week appropriate for gestational age (AGA) female infant born to a 42-year-old primigravida whose pregnancy was complicated by cervical shortening with funneling. The mother was started on bed rest, given a course of betamethasone, treated with antibiotics, and received magnesium sulfate. However, after 3 days fetal distress was noted and the infant was delivered vaginally. Delivery room resuscitation included brief bag-mask ventilation, and continuous positive airway pressure (CPAP) was started and the infant was assigned to the neonatal intensive care unit. The Apgar scores were 6 (1 minute) and 8 (5 minutes). The infant was rapidly weaned to room air while receiving CPAP. She was treated with antibiotics for 7 days, in part because of the perinatal history as well as abnormal blood count indices (initial immature-to-total neutrophil ratio 0.39, which normalized within 24 hours). The culture results remained negative. The clinical course was characterized by recurrent apnea and bradycardia, for which caffeine was administered. A cranial sonogram performed on DOL 5 revealed increased bilateral periventricular echodensities ( Fig. 2.3A ). Sonograms performed on DOL 28 showed the evolution of bilateral diffuse cystic encephalomalacia (see Fig. 2.3B ). An MRI performed at 36 weeks postmenstrual age revealed extensive cystic periventricular leukomalacia (PVL) with mild diffuse parenchymal volume loss and diffuse thinning of the corpus callosum (see Fig. 2.3C ). Placental pathology demonstrated an immature placenta with evidence of acute chorioamnionitis and funisitis.
This case illustrates the more typical ultrasonographic expression of white matter injury in the premature infant, characterized by hyperechogenicity, followed by the evolution of cystic changes in the absence of overt postnatal provocative clinical factors. Although cysts usually became apparent within the first 2 to 3 weeks of life, data have now shown the evolution of cysts beyond the first month in an increasing numbers of cases. Moreover, progressive dilation of the lateral ventricles, which in some cases is consistent with diffuse white matter injury, is also becoming more common. However, MRI indicates that white matter injury is more prevalent than is apparent from cranial ultrasonography.
Periventricular Leukomalacia
Periventricular leukomalacia refers to injury to the cerebral white matter and has long been regarded as the characteristic brain lesion of the premature infant. PVL is characterized by a focal component of necrosis with loss of cellular elements and a diffuse component with astrogliosis, microglial gliosis, and maturational injury to the premyelinating oligodendrocytes. The focal necrosis can be macroscopic in size and evolve over weeks into cystic lesions readily seen on serial ultrasounds, referred to as “cystic PVL” (see Fig. 2.2 ). The incidence of this pathology has declined over time, occurring in fewer than 5% of very low-birth-weight (VLBW) preterm infants. Focal necrosis can also be microscopic, and this type occurs more commonly and evolves into glial scars that are less readily seen on neuroimaging, referred to as “noncystic PVL.” White matter injury may also occur beyond the focal necrosis and occurs as diffuse white matter injury. This is now the most frequent form of white matter injury in preterm infants. From the early necrotic lesions, there is a widespread initial degeneration of premyelinating oligodendrocytes, followed by a compensatory increase in dysmature oligodendroglial progenitors that are not able to fully differentiate into mature myelin-producing cells. This results in poorly myelinated axons with ventriculomegaly. This diffuse component is less well characterized on imaging, even on MRI, but does include diffuse signal abnormalities and disturbances in diffusion imaging of the white matter.
Pathogenesis
Experimental and clinical observations suggest a complex interaction of vascular factors, inflammation, and the intrinsic vulnerability of the differentiating oligodendrocyte that leads to white matter injury in the preterm infant.
Vascular Factors
Several features peculiar to the premature infant are important in the vascular mechanism of PVL. The first relates to the vascular development and supply. Specifically, the penetrating branches of the anterior, middle, and posterior cerebral arteries end in border zones, which are most vulnerable to decreases in CBF. It is within these border zones that the focal necrosis of PVL typically occurs. Furthermore, the penetrating cerebral vessels, which include long branches that terminate in the deep periventricular white matter and short branches that terminate in the subcortical white matter, vary as a function of gestational age. Thus early on, at approximately 24 to 30 weeks’ gestation, the long penetrators have few side branches and limited intraparenchymal anastomosis with the short branches, resulting in border zones in white matter beyond the periventricular region. This feature may account for the more diffuse lesion noted in the smaller premature infant. From 32 weeks on, there is a marked increase in vascular supply as a result of increase in vessel length and anastomoses. It is this vascular maturation that likely accounts for the uncommon presentation of this lesion in the larger infant. A second feature relates to the limited vasodilatory response of the blood vessels supplying the white matter to increases in the arterial partial pressure of carbon dioxide (Pa co 2 ) in comparison with the vasodilatory responses of the blood vessels supplying other regions of brain, such as the medulla and gray matter, as well as a persistent decrease in CBF to white matter during the phase of reperfusion following ischemia, despite recovery in all other brain areas. Finally, impairment of CBF autoregulation, as may occur in the sick premature infant, increases the risk for ischemia to the border-zone regions of white matter during episodes of systemic hypotension. Clinically, loss of CBF autoregulation and/or decreases in CBF may occur in the sick infant secondary to events such as hypotension, acidosis, septic shock, hypocarbia, PDA, recurrent apnea, and bradycardia, and may in part explain the association of such events with PVL.
Intrinsic Vulnerability of the Differentiating Oligodendrocyte
It has been established that the premyelinating oligodendrocyte (pre-OL) is most vulnerable to injury secondary to release of numerous factors, including free radicals, excitotoxins, and cytokines. These cells undergo cell death via apoptosis, as seen in newborn animal models subjected to hypoxia-ischemia and/or infection demonstrating apoptotic cell death in immature cerebral white matter. After the initial depletion of these pre-OLs, early oligodendrocyte progenitors that are more resistant to the initial ischemic/inflammatory insult proliferate robustly in the setting of pre-OL depletion. However, this new population of pre-OLs displays maturational arrest and the pre-OLs fail to develop into mature myelin-producing oligodendrocytes, leading to failed myelination of intact axons. In a neuropathologic study, apoptosis of pre-OLs was observed significantly more often in infants dying of white matter injury than in infants without white matter injury. In the diffuse white matter lesions, neuropathology has also shown a marked prominence of activated microglia and reactive astrocytosis, as identified by immunocytochemical markers for oxidative and nitrative attacks. The presence of the activated microglia raises the possibility of a key role for these cells in the causation of the diffuse injury to the premyelinating oligodendrocyte (see later discussion).
Free Radical Injury
The prominence of activated microglia in the diffuse component of PVL suggests that these cells may be involved in the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) found in the human lesion. Microglia have been shown to be activated by ischemia and inflammation and remain activated for weeks following the insult. Activation of microglia releases ROS and RNS, which then cause pre-OL cell death. Experimental studies have demonstrated vulnerability of the pre-OL to injury by free radicals. This maturation-dependent vulnerability to injury by ROS and RNS appears to be related to deficient antioxidant defenses and acquisition of iron during development, which may result in hydroxyl radical formation. The role of free radical‒induced damage in triggering the death of the early differentiating oligodendrocyte is supported by the cryoprotection provided by the Fenton reaction. Human studies have shown a delay in the development of free radical scavengers, such as superoxide dismutase, desferrioxamine, and vitamin E, leaving tissues without the requisite antioxidant enzyme cascade following preterm birth to an oxygen-rich postnatal environment. Neonatal rat models studied on postnatal day 3 (P3) and P6 showed bilateral reduction in myelin basic protein expression with 24 hours of exposure to 80% oxygen, an effect not noted when they were studied on P10. Hyperoxia caused oxidative stress and triggered maturation-dependent apoptosis in pre-OLs, which involved the generation of ROS and caspase activation, and led to white matter injury in the neonatal rat brain. This effect could be blocked by estradiol, which produced significant dose-dependent protection by preventing hyperoxia-induced proapoptotic Fas upregulation and caspase-3 activation.
Excitotoxic Injury (Glutamate)
Glutamate can lead to the death of oligodendroglial precursors via both receptor and nonreceptor-mediated mechanisms. The nonreceptor mechanism involves intracellular entry of glutamate in exchange for cystine via activation of a glutamine-cystine exchange transporter, resulting in a decrease in intracellular cystine and thereby glutathione synthesis. The result is glutathione depletion and free radical‒mediated cell death. The receptor-mediated injury appears to be mediated via activation of 2-amino-3-[5-methyl-3-oxo-1,2-oxazol-4-yl]propanoic acid (AMPA)/kainate‒type glutamate receptors. Experimental data suggest that this form of cell death occurs only in developing and not mature oligodendroglia, related to upregulation of this receptor in oligodendrocyte precursors. It has also been shown, in an immature animal model of diffuse white matter injury, that non‒ N- methyl- d -aspartate (NMDA) receptors are present on pre-OLs that cause free radical‒mediated death of these cells when activated in vitro, and that in vivo cause death of pre-OLs when activated by hypoxia-ischemia. The relevance of this mechanism to hypoxia-ischemia‒induced white matter injury has been demonstrated in an immature rat model, in which such injury is prevented by the systemic administration of the non-NMDA receptor antagonist 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX) following termination of the insult. NMDA receptors have also been found in the processes of oligodendrocytes across its developmental lineage. Ischemia resulting in excess glutamate may result in loss of oligodendrocyte processes.
Cytokines
Cytokines released by activated microglia also participate in an important mechanism for pre-OL cell death. The paradigm of ischemia-reperfusion accompanied by a rapid activation of microglia, secretion of cytokines, and migration of inflammatory cells has been well established in animal models. Within the central nervous system, microglia release tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and IL-6. Cell culture studies suggest that TNF-α is toxic to oligodendroglia. Interferon-γ is also toxic to oligodendroglia, an effect potentiated by TNF-α. However, numerous additional cytokines, microglia, or white blood cells may be involved in this process. Indeed, in one study, increased levels of circulating proinflammatory cytokines during the first 72 hours of life were associated with arterial hypotension and with the development of brain damage as detected by ultrasonography. Increases in IL-6, IL-8, and IL-10 were associated with arterial hypotension, and increases in IL-6 and IL-8 with severe IVH. Prolonged rupture of membranes was associated with increased postnatal levels of interferon-γ, which in turn were associated with white matter injury. The potential deleterious effects of cytokines may be mediated via other mechanisms, including increased permeability of the blood-brain barrier, vascular endothelial damage, and decreased CBF to white matter after endotoxin exposure.
Maternal Fetal Infection and/or Inflammation and White Matter Injury
Both experimental and clinical evidence demonstrate an association between maternal infection/inflammation of the chorion and amnion with or without fetal vascular involvement (i.e., funisitis) and white matter injury. Thus intraperitoneal injection of lipopolysaccharides into kittens and exposing pregnant rabbits to intrauterine infection induce white matter injury similar to that observed in humans. Several clinical studies have demonstrated an association between chorioamnionitis and PVL. As in IVH, this association appears to be accentuated in the presence of funisitis. The link between chorioamnionitis may be mediated via cytokines. High levels of cytokines (IL-6 and IL-1β) have been found in the amniotic fluid, of IL-6 in cord blood, and of IL-1, IL-6, and interferon in neonatal blood of preterm infants in whom PVL or cerebral palsy develops. Microglial expression of TNF-α and IL-6 immunoreactivity is found twice as commonly in the white matter of infants with PVL as in infants without injury to the region.
In contrast to these potential deleterious effects, focal cerebral ischemia was found to be exacerbated in a mouse model of hypoxia-ischemia lacking TNF-α. Injury-induced microglial activation was suppressed in the TNF-α knockout mice. These latter observations point to the complex interrelationships between cytokines and white matter injury.
Clinical Factors Associated With PVL
Perinatal events associated with postnatal cystic PVL and/or progressive white matter injury include a history of chorioamnionitis (see earlier discussion), prolonged rupture of membranes, peripartum hemorrhage, severe fetal acidemia, hypovolemia, sepsis, hypocarbia, hemodynamically significant PDA, postnatal infection/sepsis, and recurrent apnea and bradycardia. A common feature of many of these conditions is a reduction in systemic blood pressure. Indeed, in one study, chorioamnionitis was associated with increased IL-6 and IL-1β concentrations in cord blood, elevated newborn heart rate, and decreased mean and diastolic blood pressures, and the cord blood IL-6 concentration correlated inversely with newborn systolic, mean, and diastolic blood pressures. By contrast, in a study of 14 infants in whom PVL developed, only 4 (30%) had overt evidence of postnatal systemic hypotension, and asphyxia was an uncommon finding. Other studies have also been unable to demonstrate a consistent association between hypotension and PVL.
Prevention
From the preceding discussion, it is likely that prevention of PVL will be difficult. First, it is relatively uncommon; second, as noted previously, the pathogenesis of PVL is complex ( Fig. 2.4 ); and third, the presentation is often subtle and detected only with neuroimaging. Although there is evidence pointing to an association between perinatal infection (chorioamnionitis) and PVL, the precise mechanisms linking the two remain unclear; the positive predictive value of a history of chorioamnionitis and subsequent PVL is low, approximating 10%, and many cases of infection are asymptomatic with the diagnosis established only on histologic examination of the placenta.
Related posts:
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General Supportive Management of the Term Infant With Neonatal Encephalopathy Following Intrapartum Hypoxia-Ischemia
Diagnosis and Management of Acute Seizures in Neonates
Neonatal Meningitis: Current Treatment Options
Hyperbilirubinemia and the Risk for Brain Injury
Amplitude-Integrated EEG and Its Potential Role in Augmenting Management Within the NICU
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