Early Human Development, 24 (1990) l-22 Elsevier Scientific Publishers Ireland Ltd. EHD 01085

Review Article

White matter damage in preterm newborns an epidemiologic perspective Alan Leviton” and Nigel Panethb “Deportments of Neurology. Children’s Hospitoi ond Horvord Medical School MA and Trogrom In Epidemiology ond Deportment of Pediatrics, College of Human Medicine, Michigan State University MI (U.S.A.) (Received 23 August 1989; revision received 22 May 1990; accepted 28 June 1990)

Summary Prior to 1980, white matter abnormalities of the preterm newborn were known exclusively as pathological entities, but now cranial ultrasonography can image white matter abnormalities in life. Ultrasonographic white matter echodensities and echolucencies in low birthweight babies predict later handicap (especially cerebral palsy) more accurately than any other antecedent. With the increased availability of high resolution cranial ultrasonography and the improved skill in obtaining and reading cranial ultrasonograms, rapid gains can be expected in our understanding of white matter disorders. These advances are likely to be made in the diagnosis and classification of white matter disorders and in their epidemiologic and prognostic features, topics explored in this review. preterm newborn; brain disorder; ultrasonography; lacia; cerebral palsy; intracranial hemorrhage

leukoencephalopathy;

leukoma-

Introduction Babies born in the 1950s and 1960s who weighed less than 2.0 kg at the time of birth were 13 times more likely to manifest cerebral palsy in later years than were Correspondence to: Alan Leviton, M.D., Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115-5747, U.S.A. 0378-3782/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland

heavier babies [87]. Many advances in perinatal care, including fetal heart monitoring, scalp capillary pH analyses and neonatal intensive care units, have occurred since then. Yet the rate of later cerebral palsy remains 25 to 30 times higher in infants who weigh less than 1.5 kg at birth than in full-sized newborns, and babies whose birthweight is less than 2.5 kg continue to account for about one third of all babies who later manifest cerebral palsy [ 1121. Reduction in cerebral palsy incidence depends then, to a large extent, on a better understanding of the epidemiology and pathogenesis of brain injury in newborns at highest risk, those born at least eight weeks prior to term and weighing less than 1.5 kg. Structural abnormalities of cerebral white matter that predict later handicap can now be identified with ultrasound (US) imaging performed in the neonatal intensive care unit [12,18,19,23,27,38,50,53,55,94,96,111,113,129]. As a result, these images have become the focus of epidemiologic attention. Because ultrasound scans can be obtained repeatedly without risk, hypotheses concerning the time of onset of the white matter damage leading to cerebral palsy can be generated and tested. Exposures not temporally related to the development of these abnormalities, such as events occurring after documentation of the brain lesions, can be excluded from consideration as risk factors. Moreover, the quality of data collected about exposures is likely to be higher in studies of neonatal white matter lesions than in studies of clinically-manifest cerebral palsy because of the close temporal relationship between the ultrasonographic abnormality and the earliest time that data can be collected about antecedents. New developments in brain imaging thus carry the promise of expanding our understanding of the causes of cerebral Palsy * 2. Developmental pathology of white matter Between 28 and 32 weeks of gestation, when the risk of white matter damage is especially high (v.i.), the brain undergoes time-limited maturational changes, including myelinogenesis [47], a process especially important to white matter development, because the myelin content of white matter is high. Preterm newborns who die rarely have stainable myelin in their cerebral hemispheres /13], but do have lipid-laden cells in the areas of their brain where myelin would have been found had the baby survived [61,85]. These lipid-laden cells, not discernible in the brains of infants and older children, have been named pre-myelin glial cells because of the assumption that they play a role in myelinogenesis. Perhaps the most visually obvious expression of disturbed or damaged myelinogenesis is necrosis of these pre-myelin and other glial cells in white matter. The responses to cellular injury, including exudation from damaged blood vessels and proliferation and in-migration of inflammatory and repair cells, may result in an echodense (ED) image on US [8,37,92]. If necrosis is sufficiently severe, the resultant evacuation of necrotic debris results in the formation of cavities, which are often large enough to be seen on US as an echolucency (EL) [27,32,92,118]. The higher risk of white matter necrosis in premature than in mature infants suggests that myelinogenesis is more susceptible to injury than is the maintenance of already-formed myelin. Alternatively, the histologic features of white matter nec-

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rosis might be less readily identified once myelin has been laid down, in which case the apparently higher risk in prematures would be an artifact. The most straightforward link between white matter necrosis and later cerebral palsy is anatomical. If sufficient cells destined to lay down myelin are irreparably damaged, then surviving infants may be expected to have a diminished amount of total white matter, with such consequences as large ventricles without cranial enlargement (i.e., hydrocephalus ex vacua). If the white matter reduction is extreme, the brain will be much smaller than expected, perhaps resulting in microcephaly. The handicaps the child will later manifest depend on the extent and location of white matter reduction 1211. Prominent motor handicaps (i.e., cerebral palsy) are the ones most reliably identified. Presumably, however, the full range of cognitive/ perceptive handicaps might also result from perinatal white matter damage. Another link between white matter damage and handicap derives from the observation that some children who die with profound motor and cognitive handicaps have small, unusually firm brains with grossly normal amounts of gray matter and a prominent paucity of periventricular white matter [21]. The firmness of the white matter of these brains is attributable to the presence of glial fibrils, the nervous system equivalent of scar tissue. Glial fibrils are not seen in the normal neonatal brain, nor are hypertrophic astrocytes, the cells that are thought to produce them [46]. In these children with established handicap, hypertrophic astrocytes are not seen, but the presence of glial fibrils in their small brains implies the previous presence of hypertrophic astrocytes. Hypertrophic astrocytes, however, are seen frequently in white matter that contains histologic features of necrosis, though occasionally hypertrophic astrocytes occur in isolation. The longer a baby with hypertrophic astrocytes survives, the greater the probability the white matter will have necrotic foci [76]. This raises the possibility that hypertrophic astrocytes may be an early (i.e., pre-necrotic) expression of white matter damage. The term most widely used to describe white matter damage is periventricular leukomalacia (PVL). Banker and Larroche in 1964 defined PVL as multifocal necrosis in the periventricular white matter with several additional histologic features such as retraction balls, karyorrhexis and mineralization [5]. In the ensuing years, the term has come to be used, particularly in the ultrasound literature, to describe virtually any form of injury to white matter. Although we prefer to avoid the name PVL unless it is used specifically, in discussing published papers we cite the term used by the authors. Knowledge of the evolution of white matter damage has been based on extrapolation from the patterns seen in infants dying at different ages. From these histologic studies, white matter damage appears to evolve in a regular progression from hypertrophic astrocytes in isolation to necrosis without mineralization, to PVL (as defined by Banker and Larroche), to cystic leukomalacia [3,21,106]. Support for some aspects of this pattern of progression comes from longitudinal ultrasonographic studies (of the same infants repeatedly) showing that echodensities (presumably representing necrosis) sometimes evolve into echolucencies (i.e., cavities and cysts) [27,32,118]. To unify all the histologically-defined acquired white matter disorders of infancy

4

under a single umbrella term, such as perinatal leukoencephalopathy [73,75], requires that the histologic characteristics of what were separate entities be considered different manifestations of one entity. Histologic differences between entities are thought to reflect differences in the time or magnitude of insults or differences in the cellular response of brains at different stages of development. 3. Epidemiologic studies of autopsy-defined white matter disorders The epidemiologic characteristics of all the perinatal leukoencephalopathies are not presented in this review, mainly because they add little to what is reported below about PVL, the entity characterized by necrosis. The earliest epidemiologic studies of perinatal white matter necrosis were based on data from autopsy samples. Caution is advised about generalizing from such data to the population of babies who survive, or even to infants who die but do not come to autopsy [78]. These studies are viewed as first-generation studies because they were based solely on histologically-confirmed diagnoses. Only two such epidemiologic studies have been reported. The national collaborative perinatalproject (NCPP) of NINCDS study The sample for the autopsy component of this study consisted of 560 babies registered in the NCPP who died during the first 28 postnatal days and whose brains were available for postmortem examination [3 1,431. All of these babies were born before 1967 [89] and thus before the technologic advances grouped under the rubric “neonatal intensive care” were instituted. Almost 90% of the deaths occurred within the first 48 h of life. The minimum time for histologic features of necrosis to become evident after white matter insult is not known, but some students of the topic estimate it to be 72 h [33]. Thus, by its very nature, this sample was bound to identify preferentially prenatal risk factors for PVL. Findings from this study include: A. Congenital anomaly. Three congenital anomaly variables, omphalocele, genitourinary malformations other than hypospadias and chordee, and GI malformations and related disorders, were more strongly associated with PVL than were all other variables evaluated. B. Gestational age. The gestational age group at highest risk of PVL was 28 to 3 1 weeks and the risk decreased slightly with increasing gestational age until the 39th week. Birthweight was not as good as gestational age in predicting risk of PVL. C. Postnatal age. Babies who survived the second day of life were at greater risk of necrosis than babies who died earlier. The covariates of survival beyond the second postnatal day are those now seen as occurring less commonly than expected in babies with PVL (e.g., high Apgar scores, absence of respiratory distress, absence of primary apnea). Thus, longer survival in this sample may not have obscured the identification of risk factor correlates of longer survival. Rather, longer survival may have contributed information about the minimum time needed for postnatal insults to occur and the minimum time needed following these insults for the white matter necrosis to become histologically evident. D. Bacteremia. Babies with documented bacteremia were nine times more likely to have necrotic foci in their cerebral white matter than were babies without confirmed bacteremia.

5

E. Demographics. The risk of necrotic foci increased with increasing maternal age. As housing density increased, so did the risk of necrotic foci. F. Intrapartum problems. Measures of perinatal distress including unusually low or high fetal heart rate, low Apgar scores, cardiorespiratory arrest and need for oxygen therapy were not associated with white matter necrosis in this sample. The Pittsburgh study This case-control study compared 17 cases of PVL born in 1975-6 to 83 controls [108]. The sample included 18 stillbirths, but the case/control distribution among stillbirths was not reported. None of the 33 babies who weighed less than 900 g at birth had PVL, whereas PVL was present in the brains of 24% of babies whose birthweight was between 900 and 2700 g. Only 7% (6/81) of babies who survived less than six days had PVL, compared to 58% (1 l/19) of those who survived at least six days. None of the 11 other risk factors evaluated (including sepsis and low Apgar scores) was prominently associated with PVL in this study of 17 cases.

4. Ultrasonography in the study of white matter lesions

Computerized tomography (CT) and magnetic resonance imaging (MRI) each require that the baby be transported out of the neonatal intensive care unit. As a consequence, physicians are reluctant to obtain CT scans routinely on preterm babies who are physiologically unstable. Inferences based on a study in which only some babies are examined with an imaging procedure are severely limited [104]. In addition, unique water content characteristics of preterm white matter limit the value of MRI [52]. As in any science, advances in epidemiology are usually incremental [16,64]. Technologic advances, however, can sometimes facilitate large and rapid increments. High resolution ultrasonographic equipment has allowed epidemiologic studies of white matter damage in the living newborn. Cranial ultrasonography, a noninvasive imaging procedure, does not require anesthesia or sedation, does not involve radiation exposure and can be performed at the isolette side. The prognostic value of cranial ultrasound scans has been established for parenchymal lesions [71] (v.i. and Tables II and III). A. Techniques Before 1983, ultrasonographic scans of the brain (almost invariably obtained with transducers of 5 mHz or lower frequency) did not provide high quality images of periventricular white matter. Since then, the improved resolution provided by 7.5-mHz transducers allows echodensities and echolucencies in the cerebral white matter to be seen more clearly than before [52]. In addition, recognition of the importance of white matter damage has prompted ultrasonographers to extend their scanning planes more peripherally than is needed for the diagnosis of germinal matrix and intraventricular hemorrhage. A broader range of white matter abnormalities can now be identified because of improved techniques and equipment.

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Diagnostic criteria (a) White matter echodensities. Although a variety of definitions of parenchymal echodensity (sometimes known as increased parenchymal echogenicity) have appeared in the literature [4,28,32,34,53,83,91,92], no consensus has yet been achieved about the optimal definition. The issue of size of the echodensity is rarely addressed. This is unfortunate because single large echodensities (frequently misnamed as grade IV hemorrhage in the Papile classification [95]) may not have the same origin or the same antecedents as the entity characterized by multiple, small, often bilateral echodensities (frequently called PVL). The large unilateral echodensity is frequently first seen hours after recognition that the ipsilateral lateral ventricle is distended and diffusely echodense [56]. Hemorrhagic infarction is sometimes seen on postmortem examination of the tissue represented by the echodensity [56,103]. This infarction has been attributed to impaired blood flow in the area where the medullary veins in the periventricular white matter become confluent and join the terminal veins in the subependymal region [49,117,126]. Caution in interpretation is advised, however, because some reports comparing ultrasound with autopsy have noted that massive unilateral intraventricular hemorrhage can simulate unilateral large parenchymal echodensity [23,91,100]. An interesting research question is whether the disorder characterized by a single large echodensity, which probably represents unilateral hemorrhagic infarction, has the same antecedents as that characterized by multiple small paraventricular echodensities, which probably represent multiple foci of necrosis (Fig. 1). A particular kind of diffuse white matter echodense lesion has been given the name “prolonged flare” [122]. This has been defined as “relative increased echodensity in the periventricular region seen in both coronal and parasagittal views and persisting for at least two weeks, but not undergoing cystic degeneration”. Histologic examination of brains with this ultrasonographic image has identified spongiosis and microcalcification of the periventricular white matter [120], but these findings may not be specific and could represent agonal changes or staining artifact

Pm About 1% of preterms have focal areas of extremely high echogenicity scattered throughout the periventricular white matter [51]. These images, generally bilateral and symmetrical, and tending to appear one to three weeks later in life than peri/ intraventricular hemorrhage, are considered to represent PVL in its precystic stage. They often appear to be forerunners of echolucencies and therefore should be distinguished from the benign normal variants described immediately below. (b) Normal variants. The cranial ultrasound scan of many preterm babies has a peritrigonal echodense halo that is invariably less echogenic than the choroid plexus and tends to be homogeneous [5 11, or appear as fine brush strokes [28]. In addition, the lateral borders are poorly defined and medially a thin anechoic line (possibly of cerebrospinal fluid) separates the halo from the choroid plexus [5 11. Periventricular halos are also seen commonly in clinically healthy term infants [69]. Support for the impression that they are artifacts comes from the observation of halos in only one view [28]. (c) Echolucencies. Definitions of echolucent lesions [22,32,53,115] are less abun-

7

Fig. 1. In this posterior coronal scan are zones of increased echogenicity adjacent to the lateral and superior borders of the lateral ventricle. These echodensities appear white. The single small round black (echolucent) area within the echodense corner of the right lateral ventricle may be the first of several to develop.

dant than definitions of echodensities, perhaps because they are less subject to interobserver variation. The terms cyst and cavity are used interchangeably in the ultrasound literature. True cysts (i.e., cavities lined with a distinct membrane or tissue) probably constitute only a minority of hypoechoic (or echolucent) regions in the parenchyma. Although convincing evidence has yet to be provided, porencephaly (i.e., a cavity communicating with a lateral ventricle) in preterm newborns tends to be viewed as a posthemorrhagic phenomenon [30,41]. Subcortical cysts are viewed as distinct from periventricular cysts both because of their location and their tendency to occur in fullterm newborns [121]. An ischemic origin for the subcortical cysts is suggested by one study that documented hypotension prior to the development of the echolucen-

8

ties [121] and the location of these echolucencies in “end zones” of deep penetrating branches of small arteries [21,116].

C. Ultrasonograph/pathology correlations Studies of the natural history of parenchymal lesions seen on cranial ultrasound scans suggest that densities precede lucencies by days to weeks [27,32,118]. The echodensities are usually viewed as representing early stages of tissue necrosis, with the increased density representing proliferation and in migration of inflammatory/ scavenger and repair cells and the presence of extravascular blood and/or proteinrich fluids (due to diminished vascular integrity) [24,37,58,69,91,92,103,120]. The choice of names used to descre ED terms appears to reflect the authors’ assumption that they know the histology of the ED. The histology represented by ultrasonographic echodensities includes: parenchymal hemorrhage, infarction, edema, and a variety of histologic features characteristic of early necrosis and ischemia [ 10,24,37,92,103,120]. ED, therefore, should be viewed as a heterogeneous group of disorders. Accompanying ventriculomegaly increases the probability that ED reflects necrosis 1921. Until the degree of correlation between ultrasonographic images and histopathology improves (v.i.), we recommend use of generic terms such as echodense, echogenics, or hyperechoic zones and echolucent or hypoechoic areas.

D. Classification of uitrasonographic images of white matter As in many rapidly growing fields, time is needed to develop a consensus about what is the most clinically (let alone, epidemiologically) useful classification of echodensities and echolucencies. Among its other attributes, any proposed classification should be so constructed to minimize both inter- and intraobserver variability [99]. Until a widely-accepted classification is available, we encourage ultrasonographers to avoid interpretation labels (e.g., grade IV IVH, PVL). Purely descriptive terms seem more appropriate for the time being.

5. Epidemiology of US-diagnosed white matter abnormalities Seven published reports compare the experiences and characteristics of preterm infants with ED and/or EL to those of their peers who did not develop these ultrasonographic images (Table I). Each of the studies reported is characterized by a small number of babies. The study with the largest number included among its 52 cases 25 babies who had persistent flare [123]. Although the authors claim “that the risk factors for prolonged flare are similar to those for PVL”, no data are provided to support that claim. Ellis and his colleagues estimate that at least seven days following insult are needed to develop subependymal cysts and eight days are needed for microcavities 1331. Ultrasonographic assessments would lead to estimates that are considerably longer {25,32,40,91,118]. Thus, Bejar and his colleagues feel justified in considering periventricular echolucencies evident before the end of the third postnatal day as an expression of “antenatal white matter damage” [9]. The risk of this entity was 9.4fold greater in preterms whose amniotic fluid was purulent (incidence of 75%) than

9 TABLE I A summary of the findings of seven recent studies of the antecedents/correlates lucencies (EL). Antecedent/correlate

Citation Number of cases Placental vast. anastomoses* Antepartum hemorrhage (includes abruption) Funisitis/amnionitis Abdominal delivery 5 minute Apgar < 5’or 6b (or umb. art. pH < 7.15)b or “birth asphyxia”’ Postnatal Pao, < 40 Postnatal pH < 7.15’or 7.2b Hypotension’/transfusionb Anemia Pneumothorax Recurrent apnea Hyaline membrane disease Mechanical ventilation Patent ductus arteriosus Sepsis Necrotizing enterocolitis Surgery Maximum bilirubin Coagulation disorder Older age/longer survival

of echodensities (ED) and

Point estimates of odds ratios of EL and ED EL

ED(EL)

EL

EL

ED

EL

[1301 7

VW

[I71

[91

WI

15

i251 17

w31

39 (35)

52

13 t

25

3.6

2.2

6.0

5.1s 0 3.6’ @.b

3.0”

** 0.2

**

3.W 1.0

3.9

**a

2.3b

p

P P

2.8

EL

t

2.0”

4 0.9

2.1

2.0 4.1 1.3 3.3 2.9 3.4

1.5

0.7

7.7 2.9

t

t

2.9 11.7

t

***

7.3

** t t t t

*In twins. **Not increased. ***The longer the need for ventilatory assistance, the greater the risk of EL. tbIncreased or decreased risk (The authors stated the direction, but not the magnitude.)

in those without purulent amniotic fluid (incidence of 8%). Preterms whose placentas had vascular anastomoses were 6.8 times more likely to have antenatal white matter damage than were preterms without these placental anomalies (50% versus 7.4%). Other findings support the view that some white matter damage has an antenatal origin [7,10,63,68,1143. The other six studies of antecedents and correlates of periventricular echodensities and echolucencies did not distinguish between antenatal and postnatal lesions. Indeed, the timing of ultrasonographic documentation of the white matter lesions is not always clear, leaving doubt about which postnatal problems might actually be sequelae of the pathologic process imaged on US. Antepartum vaginal bleeding, or documentation of a retroplacental clot, has been repeatedly associated with EL [17,10!3,130], suggesting that antepartum dis-

10

turbances contribute to the risk of white matter damage. The study of the largest number of ED cases, however, did not show a relationship with antepartum vaginal bleeding [123]. Abdominal delivery, sometimes a covariate of vaginal bleeding immediately prior to birth, was associated with increased risk of EL in only one study [ 1301. In all four studies in which they were evaluated, a five minute Apgar of less than 5, or an umbilical artery pH of less than 7.15 was associated with increased risk of EL [17,26,109,130]. In two of these studies, babies with EL were no more likely than their peers to have a postnatal Pao, less than 40 [17,130], although in one of them, postnatal acidosis (identified as pH less than 7.15) was more common than expected in EL babies [130]. Hypocarbia was associated with EL in one study [ 171, whereas hypercarbia was associated with ED [ 1231but not with EL [ 1301. Odds ratios are estimates of the probability of a disorder (e.g., ED or EL) in those with a characteristic relative to the probability in those without the characteristic. In two reports, babies were two to four times more likely to have ED or EL if they had pneumothorax, recurrent apnea, patent ductus arteriosus or required mechanical ventilatory assistance than if they did not have these characteristics [26,109]. Recurrent apnea, with its need for mechanical ventilation, could be a consequence rather than an antecedent of EL. Two hypotheses from studies based on postmortem examinations have been evaluated to a limited extent in one or another of these seven studies based on diagnosis during life. Weindling and his colleagues found that none of their seven cases of leukomalacia had documented hypotension [ 1301. On the other hand, cases of extensive cystic leukomalacia evaluated by de Vries’ group were much more likely than babies without this ultrasonographic diagnosis to have had documented hypotension [26]. Cases of periventricular leukomalacia assessed by Calvert and his colleagues were more likely than their peers to have received a transfusion [ 171. Because fragile preterms are likely to be given transfusions for hypotension, transfusion may be a marker for hypotension. In the most recently published report about antecedents, hypotension was defined as mean blood pressure below the 10th percentile for weight and postnatal age sustained for two consecutive hours during the first 96 h of life [ 128). Babies with hypotension were twice as likely as others to have what the authors group as periventricular ischemic lesions, including large (usually irregular) ventricles ‘after one month of age, multiple (usually small) cysts and large (usually solitary) cysts. Perhaps if they evaluated the relationship between “ischemic” lesions and hypotension with multivariate models that included survival (or duration of survival), as they did for an evaluation of the relationship between intraventricular hemorrhage and “ischemic” lesions, then the authors might have obtained a more accurate estimate of the contribution of hypotension to the occurrence of EL. The second hypothesis concerned infection. Compared to babies without bacteremia, those with bacteremia were estimated to be 3.4 times more likely to have ischaemic brain lesions (i.e., ED) [ 1091. In another sample, necrotizing enterocolitis (a risk factor for bacteremia) was strongly associated with extensive cystic leukomalacia (i.e., EL) [26].

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A hypothesis generated by the NCPP was that babies with white matter damage were more likely than others to have intracranial hemorrhage. This finding might have been an artifact of selection for autopsy [43,78]. In samples of newborns who have not died, however, another kind of selection may produce the impression of an association between the two. Infants with intracranial hemorrhage are more likely than babies without hemorrhage to receive late cranial ultrasound scans (this bias is sometimes referred to as diagnostic suspicion bias [104] or detection bias [54]). This alone should provide a greater opportunity to diagnose white matter damage. Consistently, babies with ED are more likely than babies without ED to have intracranial hemorrhage (usually described as grade III/IV) [9,17,56,109, 120,123,125,128]. This may be a tautology because grade IV hemorrhage is one of the descriptive terms commonly assigned to large unilateral ED [ 1261. Any explanation of the association of intracranial hemorrhage with white matter damage must consider the prominent tendency of hemorrhage to antedate white matter injury. One hypothesis incorporating this temporal relationship is that the hemorrhage impedes venous return, resulting in venous infarction and subsequent white matter injury [49,98,105]. An alternative is that one does not cause the other, but rather that they share common risk factors. Indeed, intracranial hemorrhage and white matter injury might have their origin at the same time, but because hemorrhage occurs within minutes to hours and the ultrasonographic appearance of white matter injury is dependent on vascular and cellular responses to injury that may take days, the hemorrhage is evident several days before white matter injury is identified

PI. A recent clinical trial of high frequency oscillatory ventilation among preterm newborns requiring ventilatory assistance found that grades III and IV intracranial hemorrhage and PVL occurred more commonly in babies who received high frequency ventilation than in babies who received conventional ventilation [58]. One interpretation is that high frequency ventilation increases the risk of major intracranial hemorrhage, and that this in turn increases the risk of PVL. Another is that the necrotizing tracheobronchitis sometimes seen in babies who receive high frequency ventilation [l l] increases the risk of bacteremia, which in turn contributes to the occurrence of PVL. A third possibility is that hypocarbia, via reduced cerebral blood flow, increases the probability of ischemia and its consequences [55]. Two ultrasonographic studies permit some estimation of gestational age and birthweight specific rates of EL. In the study reported by Weindling and his associates, the peak rate of EL occurred in babies of gestational age 27-28 weeks [ 1301. Among babies reported by Bejar and his colleagues, those who weighed less than 1 kg at birth were at highest risk of white matter damage, whether evident before or after the fourth day [9]. The highest rate reported by Weindling and his coinvestigators occurred in babies weighing 1.0-1.5 kg [130]. Five of the reports provided only univariate analyses and no attempt appears to have been made to deal with confounding or interaction. Heterogeneity of cases and small sample sizes limit many of the studies. Thus, the seven early studies of USdefined white matter damage have prominent limitations and represent exercises’in hypothesis generation.

12 A.

Prematurity

and white

matter

damage

have

the

same antecedents.

PVL

Examples Risk

of

Antecedents

factors

for

congenital

infection

(e.g.,

Placental

abnormality

group

malformation

B streptococcus,

Ureaplasma)

Bleeding Fetal-fetal

transfusion

Endocrine

B.

Prsmature are

infants

fuiiterm

disturbance

are

more

vulnerable

to

physiologic

disturbances

infants.

Physiologic

I ty 0

Prematur

Examples

of

Anaerobic

Toxic

Physiologic

Disturbance

____3

Disturbances

metaboiism/acidosis

Difficulty

regulating Inhibition

cerebral

of

blood

flow

myellnogenesis

Shock

c.

Early

brain

than

damage

Antecedent

leads

premature

Brain

I

Examples

to

of

delivery

Damage __I,

Prematurity

Antecedents

Risk

factors

for

chromosomai

Risk

factors

for

congenital

aberratlons anomalies

Fig. 2. Models that explain the increased prevalence of white matter damage in preterm babies.

PVL

13

Models of the relationship between prematurity and white matter disorders (Fig. 2) Hypotheses about the origins of PVL must explain the increased risk in prematurely born babies. Indeed, these hypotheses can be trichotomized according to the role prematurity plays in increasing PVL risk. In one set of hypotheses, grouped under the heading “Prematurity is an epiphenomenon,” prenatal influences contribute both to white matter damage and to preterm delivery. In this model, preterm delivery is not causally linked to white matter damage, but is another consequence of the same group of antecedents. The second set of hypotheses emphasizes the vulnerability of the preterm infant. Vulnerability here can be viewed as the interaction of preferential susceptibility to the occurrence of physiologic insults, with a lesser tolerance for these insults by preterm infants. The third set of hypotheses is characterized by the assumption that prenatal brain damage increases the probability of the early onset of labor. The three models are not mutually exclusive. Model A: “Prematurity is an epiphenomenon ” Recent epidemiologic studies of prematurity have suggested that the vaginal flora of women who deliver prematurely differs from those of women who carry to term [82,119]. Some of these organisms cultured with increased frequency from the mothers of preterm infants are associated with an increased risk of neonatal morbidity [65,66,127]. Although not yet confirmed, antibiotic prophylaxis given to subsamples of women at high risk of a preterm delivery may increase the probability of carrying to term [83]. Women with gestational urinary tract infection, especially if accompanied by fever, were at increased risk in the NCPP of delivering a child who had one or more manifestations of perinatal leukoencephalopathy [73,75,77]. In addition, among white children in the NCPP sample followed until age seven years, mental retardation was associated with maternal urinary tract infection [14]. Group B streptococcal infection, linked in some studies to preterm delivery [62,101], has also been documented prior to the development of EL [36]. Thus, what contributes to prematurity (e.g., maternal genitourinary infection) may also contribute to PVL. Model B: ‘Prematurity is an indicator of vulnerability” This group of hypotheses is characterized by the assumption that low gestational age conveys information about heightened vulnerability. Three correlates of this vulnerability are described below. Model BI: Disturbances of cerebral bloodflaw. The “distressed” preterm infant has limited capability to regulate cerebral blood flow [1,55,80,97]. Thus, a wide variety of factors that prompt a baby to be viewed as “distressed” might contribute to the risk of white matter damage. Friede has emphasized that cyst formation reflects the tendency of immature white matter to cavitate rather than cicatrize after exposure to an ischemic insult [42]. The histologic characteristics of PVL [5] and the abnormalities of adjacent blood ‘vessels found in postmortem injection studies [ 1161 also support an ischemic origin for PVL. The subcortical distribution of cysts seen in mature infants [121] and in preterm babies [25] is often in the border zones between the three cerebral arteries. Not yet determined is whether deeper cysts also reflect a disturbance to cerebral blood flow.

14

A number of anecdotal reports are in keeping with the hypothesis that circulatory disturbances are associated with neonatal cystic encephalomalacia or PVL. These include case reports of neonatal white matter lesions following maternal vaginal bleeding [S], bee sting maternal anaphylaxis [35], fetal and neonatal cardiac arrhythmias [29,107,124], cord prolapse [39], intrauterine death [102] and extracorporeal membrane oxygenation [67]. The surviving sibling of a co-twin dying in utero also appears to be at special risk of white matter injury [2,7,68,133]. As described earlier in this paper, maternal vaginal bleeding and the baby’s receipt of (or perhaps the need for) a transfusion were found to be antecedents of echodensities. The most convincing laboratory study related to the impaired cerebral blood flow hypothesis of PVL comes from a study of pups made hypotensive by exsanguination [ 1341. The regional cerebral blood flow was decreased in the white matter, but not in the gray matter. This suggests that hypotension could account for damage to white matter while cortical integrity is preserved. Model B2: Infection. White matter destruction occurs not only in children with meningitis [ 15,l lo], but also in children who have infection that does not appear to involve the brain directly [72,73,75,77]. Neonatal sepsis is often associated with hypotension and thus, neonatal infection could increase the risk of white matter damage simply via brain ischemia. In addition, bacterial endotoxins might have specific effects on cerebral blood flow and other consequences of severe infection, such as disseminated intravascular coagulation, could contribute to white matter damage WI Support for the concept that bacterial toxins adversely affect developing white matter has come from studies of animals given lipopolysaccharides (i.e., endotoxin) derived from E. coli [44,45]. Lipopolysaccharides have a number of cytotoxic properties [81,86]. One sequence of events begins with lipopolysaccharide injuring the endothelium of vessels supplying the brain. This, in turn, allows lipopolysaccharide to gain access to pre-myelin glial cells, which because of their role in myelinogenesis, are especially sensitive to the effects of lipopolysaccharides. The association between congenital anomalies and PVL [48,67,73-751 might reflect the tendency of babies with congenital malformations to be exposed to bacterial infection. Babies with omphalocele and those with congenital heart lesions requiring early surgical correction are at increased risk of infection and subsequent sepsis [57,60,131]. Model B3: Hypoxia/asphyxia/acidosis. As noted above, babies with ultrasonographic echolucencies are more likely than their peers to display markers of birth depression (Table I). Postnatal hypoxia, however, has not been clearly related to white matter damage, although acidosis and hypercarbia have each been reported to be more common in babies with ED or EL than in controls. Still unknown is whether babies with low Apgar scores manifest adaptive reflex impairments attributable to preexisting white matter damage, or whether hypoxia, acidosis and hypotension that accompany very low Apgar scores contribute to the occurrence of white matter damage in previously intact babies. Model C: Early brain damage leads to prematurity Some of the identifiable risk indicators of perinatal white matter histologic

15

abnormalities [73,75] and of cerebral palsy [88,93], such as congenital anomalies, clearly antedate labor and delivery. Both shortened and prolonged pregnancies have been associated with preexisting central nervous system lesions and with chromosomal aberrations [79,90,132]. Thus, in addition to producing cerebral palsy syndromes, insults to early brain development (some of which result in white matter necrosis) might also promote the premature onset of labor. 6. Prognosis Cystic white matter disorders characterized by single or multiple echolucent regions on US, have proven powerful predictors of adverse neurological outcome. In some studies, these lesions have been associated with a risk of cerebral palsy as high as 100% (Table II). The impressiveness of these findings must be tempered by the recognition that cystic lesions are rare. They occur in only 3-7% of VLBW infants [50,115,129] and thus probably account for only a portion of the handicap arising in this population. Abnormally echodense areas of white matter are more common than echolucenties (occurring in IO-18% of VLBW infants) [50,109], but their clinical significance is much less straightforward than is the case for echolucencies. Echodense and echolucent lesions are linked, echodensity often preceding echolucencies such as porencephaly and cystic PVL [19,118,122,130]. However, not all echodensities evolve into lucent lesions and not all lucencies are preceded by obvious echodensities. Echodense parenchymal lesions are, like echolucent lesions, generally predictive of handicap, but vary in their predictive power, depending on the definition of the lesions used (Table III). For example, in two separate studies, only 8% of babies with “flares” later had significant motor handicap [ 19,501.

TABLE II The percent of children with echohtcent parenchymal lesions who later have cerebral palsy. First author

Year

Citation

De Vries

1985

[221

10

Graziani

1985

[531

15

Bozynski Weindling Smith Graham

1985 1985 1986 1987

Fawer Stewart Cooke

1987 1987 1987

Total

1121 (1291

N

4 8

11111 PO1

16 13 8

[381

11 10

11131 [191

32

127

Lesion description

Survivors with cerebral palsy

Extensive or subcortical PVL Large periventricular cysts or porencephaly PVL Periventricular cysts PVL Cystic PVL Multiple cysts Extensive PVL cysts Porencephalic cysts

100% 80%

100% 1OO”lo 88”i’o 62% 88% 73010 80% 69% 80%

16 TABLE 111 Echodense parenchymal lesions and the risk of subsequent cerebral palsy. First author

Year

Citation

N

Lesion description

Papile Pape Catto-Smith

1983 1985 1985

[%I

17 20 3

Guzzetta Graham

1986 1987

IJO1

22 3

Cooke

1987

[191

32

Grade IV cerebral IVH Grade IV IVH Intracerebral hemorrhage Periventricular IPE Parenchymal hemorrhage Parenchymal hemorrhage or extension

Total

I941 1181

WI

97

Survivors with cerebral palsy 76% 40%

67% 86% loos70 63%

67%

A more complete picture of the relationship between US abnormalities and cerebral palsy requires studies that not only ascertain the frequency of cerebral palsyfollowing ED or EL, but also how often cerebral palsy is preceded by ED or EL. In one follow-up study, ED or EL was seen in 35% of cases of cerebral palsy [113]. Collclusions In summary, ultrasonographically-defined abnormalities of the peri/paraventricular white matter predict later motor (and perhaps cognitive) handicap. We do not yet know what proportion of “cerebral palsy” can be attributed to echodensities and echolucencies in preterms. Recent developments in routine imaging of preterm cerebral white matter promise to make a major contribution to (a) predicting which babies will have later handicaps, (b) identifying antecedents of these handicaps and perhaps thereby, (c) preventing neurologic handicaps in preterm newborns. Note added in proof Since the time this manuscript was accepted for publication, an epidemiologic study of different forms of cerebral palsy has identified the predictive value of a late ultrasound scan, and of amnionitis, necrotizing enterocolitis and septicemia (R.W.I. Cooke (1990): Arch. Dis. Child., 65,201-206). References 1 Altman, D.I. and Volpe, J.J. (1987): Cerebral blood flow in the newborn infant: measurement and role in the pathogenesis of periventricular and intraventricular hemorrhage. Adv. Pediatr., 34, 111 -138.

17

6

7 8

9 10 11 12

13

14 15 16 17 18 19 20 21 22 23 24 25 26 27

Amiel-Tison, C. (1983): Multicystic encephalomalacia as a complication of twin pregnancy. Gynec. Reprod. Biol., IS, 279-280. Armstrong, D. and Norman, M.G. (1974): Periventricular lcucomalacia in neonates. Complications and sequelae. Arch. Dis. Child., 49,367-375. Baarsma, R., Laurini, R.N., Baerts, W. and Okken, A. (1987): Reliability of sonography in nonhemorrhagic periventricular leucomalacia. Pediatr. Radiol., 17, 189-191. Banker, B.Q. and Larroche. J.C. (1962): Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch. Neurol., 7.386-410. Barth, PG., Stam, F.C., Oosterkamp, R.F. et al. (1980): On the relationship between germinal layer haemorrhage and telencephalic leucoencephalopathy in the preterm infant. Neuropadiatrie. 11, 17-26. Barth, PG. (1984): Prenatal elastic encephalopathies. Clin. Neurol. Neurosurg., 86,65-75. Bejar, R. Coen, R.W., Merritt, T.A. et al. (1986): Focal necrosis of the white matter (periventricular leukomalacia): sonographic, pathologic and electroencephalographic features. Am. J. Neuroradio]., 7, 1073-1080. Bejar, R., Wozniak, P., Allard, M. et al. (1988): Antenatal origin of neurologic damage in newborn infants. I. Preterm infants. Am. J. Obstet. Gynecol., 159,357-33. Bejar. R., Wozniak, P., Allard. M. and Vaucher, Y. (1986): Antenatal white matter necrosis. Ann. Neurol., 20.436437. Boros, S.J., Mammel, M.C., Coleman, J.M. et al. (1985): Neonatal high-frequency jet ventilation: four years’ experience. Pediatrics, 75,657-663. Bozynski, M.E., Nelson, M.N., Matalon, T.A. et al. (1985): Cavitary PVL: incidence and shortterm outcome in infants weighing less than or equal to 1200 grams at birth. Dev. Med. Child Neurol., 27,572-577. Brody, B.A., Kinney, H.C., Kloman, A.S. and Giles, F.H. (1987): Sequence of central nervous system myelination in human infancy. I. An autopsy study of myelination. J. Neuropathol. Exp. Neurol., 46,283-301. Broman, S., Nichols, P.L., Shaughnessy, P. and Kennedy, W. (1987): Retardation in Young Children: A Developmental Study of Cognitive Deficit. Lawrence Erlbaum Associates, Hillsdale. NJ. Buchan, G.C. and Alvord, E.C. Jr. (1969): Diffuse necrosis of subcortical white matter associated with bacterial meningitis. Neurology, 19, 1-9. Buck, C. (1975): Popper’s philosophy for epidemiologists. Int. J. Epidemiol., 4, 159-68. Calvert, S.A., Hoskins. E.M., Fong, K.W. et al. (1987): Etiological factors associated with the development of PVL. Acta Paediatr. Stand., 76,254-259. Catto-Smith, A.G., Yu, V.Y.H.. Bajuk, B. et al. (1985): Effects of neonatal periventricular hemorrhage on neurodevelopmental outcome. Arch. Dis. Child., 60,8-l 1. Cooke, R.W.L. (1987): Early and late cranial US appearances and outcomes in VLBW infants. Arch. Dis. Child., 62,931-937. Corrigan, J.J., Jr. (1979): Activation of coagulation and disseminated intravascular coagulation in the newborn. Am. J. Pediatr. Hematol. Oncol., 1,245-249. De Vries, L.S., Connell, J.A., Dubowitz, L.M.S. et al. (1987): Neurological, electrophysiological and MRI abnormalities in infants with extensive cystic leukomalacia. Neuropediatrics, 18,61-66. De Vries, L.S., Dubowitz. L.M.S., Dubowitz, V. et al. (1985): Predictive value of cranial ultrasound; a reappraisal. Lancet, 2,137-140. De Vries, L.S., Regev, R., Connell, J.A. et al. (1988): Localized cerebral infarction in the premature infant. Pediatrics, 81,36-40. De Vries, L.S., Regev, R. and Dubowitz, L.M.S. (1986): Late onset cystic leucomalacia. Arch. Dis. Child., 61,298-299. De Vries, L.S., Regev, R., Dubowitz, M.S., Whitelaw, A. and Aber, V.R. (1988): Perinatal risk factors for the development of extensive cystic leukomalacia. Am. J. Dis. Child., 142,732-735. De Vries, L.S., Regev, R., Pennock. J.M. et al. (1988): Ultrasound evolution and later outcome of infants with periventricular densities. Early Hum. Dev., 16,225-233. DeReuck, J., Chatta, A.S. and Richardson, E.P., Jr. (1972): Pathogenesis and evolution of periventricular leukomalacia in infancy. Arch. Neurol., 27,229-236.

28 DiPietro, M.A., Brody, B.A. and Teele, R.L. (1986): Peritrigonal echogenic “blush” on cranial sonography: pathologic correlates. A.J.N.R., 7,305-310. 29 Donn, S.M. and Bowerman, R.A. (1986): Association of paroxysmal supraventricular tachycardia and PVL. Am. J. Perinatol., 3,50-52. 30 Donn, S.M. and Bowerman, R.A. (1982): Neonatal posthemorrhagic porencephaly: ultrasonographic features. Am. J. Dis. Child., 136,707-709. 31 Dooling, E.C. (1983): Characteristics of the neuropathology sample. in: The Developing Human Brain: Growth and Epidemiologic Neuropathology, pp. 37-40. Editors: F.H. Gilles, A. Leviton and E.C. Dooling. Wright-PSG, Littleton, MA. 32 Dubowitz, L.M.S., Bydder, G.M. and Mushin, J. (1985): Developmental sequence of periventricular leukomalacia. Arch. Dis. Child., 60,349- 355. 33 Ellis, W.G., Goetzman, B.W. and Lindenberg, J.A. (1988): Neuropathologic documentation of prenatal brain damage. Am. J. Dis. Child., 142,858-866. 34 Enzmann, D., Murphy-Irwin, K. and Stevenson, D. (1985): The natural history of subependymal germinal matrix hemorrhage. Am. J. Perinatol., 2, 123-133. 35 Erasmus, C., Blackwood, W. and Wilson, J. (1982): Infantile multicystic encephalomalacia after maternal bee sting anaphylaxis during pregnancy. Arch. Dis. Child., 57,785-787. 36 Faix, R.G. and Donn, S.M. (1985): Association of septic shock caused by early-onset group B streptococcal sepsis and periventricular leukomalacia in the preterm infant. Pediatrics, 76, 415419. 37 Fawer, C.L., Calame, A., Perentes, E. and Anderegg, A. (1985): Periventricular leukomalacia: a correlation study between real-time ultrasound and autopsy findings. Periventricular leukomalacia in the neonate. Neuroradiology, 27,292-300. 38 Fawer, CL., Diebold, P. and Calame, A. (1987): PVL an4 neurodevelopmental outcome in preterm infants. Arch. Dis. Child., 62,30-36. 39 Ferrer, I. and Navarro, C. (1978): Multicystic encephalomalacia of infancy. J. Neurosci., 38, 179 -189. 40 Fischer, A.Q., Anderson, J.C. and Shuman, R.M. (1988): The evolution of ischemic cerebral infarction in infancy: a sonographic evaluation. J. Child. Neurol., 3, 105-109. 41 Fleischer, A.C., Hutchison, A.A., Bundy, A.L. et al. (1983): Serial sonography of posthemorrhagic ventricular dilatation and porencephaly after intracranial hemorrhage in the preterm neonate. Am. J. Roentgenol., 141,451-455. 42 Friede, R.L. (1975): Developmental Neuropathology. Springer-Verlag, Vienna. 43 Fulchiero, A. and Leviton, A. (1983): Selection bias in the creation of the NINCDS Collaborative Perinatal Project neuropathology sample. In: The Developing Human Brain. Growth and Epidemiologic Neuropathology, pp. 22-31. Editors: F.H. Gilles, A. Leviton and E.C. Dooling. John Wright-PSG, Littleton, MA. 44 Gilies, F.H., Averill, D.R. and Kerr, C.S. (1977): Neonatal endotoxin encephalopathy. Ann. Neurol., 2,49-56. 45 Gilles, F.H., Leviton, A. and Kerr, C.S. (1976): Susceptibility of neonatal feline telencephalic white matter to a lipopolysaccharide. J. Neurol. Sci., 27, 183-191. 46 Gilles, F.H. and Murphy, S.F. (1%9): Perinatal telencephalic leucoencephalopathy. J. Neurosurg. Psychiatry, 32,404-413. 47 Gilles, F.H. (1983): Changes in growth and vulnerability at the end of the second trimester. In: The Developing Human Brain. Growth and Epidemiologic Neuropathology, pp. 316320. Editors: F.H. Giles, A. Leviton and E.C. Dooling. John Wright-PSG, Littleton, MA. 48 Goodlin, R.C., Heindrick, W.P., Papenfuss, H.L. and Kubitz, R.L. (1984): Fetal malformations associated with maternal hypoxia. Am. J. Obstet. Gynecol., 149,228-229. 49 Gould, S.J., Howard, S., Hope, P.L. and Reynolds, E.O.R. (1987): Periventricular intraparenchymal cerebral haemorrhage in preterm infants: the role of venous infarction. J. Pathol., 151, 197 -202. 50 Graham, M., Levene, M.I., Trounce, J.Q. et al. (1987):‘Prediction of cerebral palsy in VLBW infants: Prospective ultrasound study. Lancet, 2,593-595.

19 51 Grant, E.G., Schellinger, D., Richardson, J.D. et al. (1983): Echogenic periventricular halo: normal sonographic finding or neonatal cerebral hemorrhage? Am. J. Neuroradiol., 4,43--46. 52 Grant, E.G. and Schellinger, D. (1985): Sonography of neonatal periventricular leukomalacia: recent experience with a 7.5 mHz scanner. Am. J. Neuroradiol., 6,781-785. 53 Graziani, L.J., Pasto, M., Stanley, C. et al. (1986): Neonatal neurosonographic correlates of cerebral palsy in preterm infants. Pediatrics, 78,88-95. 54 Greenland, S. and Neutra, R. (1981): An analysis of detection bias and proposed corrections in the study of estrogens and endometrial cancer. J. Chron. Dis., 34,433-438. 55 Greisen, G., Munck, H. and Lou, H. (1986): May hypocarbia cause ischaemic brain damage in the preterm infant? Lancet, 2,460. 56 Guzzetta, F., Shackelford, G.D., Volpe, G. et al. (1986): Periventricular IPE in the premature newborn: critical determinant of neurologic outcome. Pediatrics, 78,995--1006. 57 Hatch, E.I., Jr. and Baxter, R. (1987): Surgical options in the management of large omphaloceles. Am. J. Surg., 153.449-452. 58 The HIFI Study Group. (1989): High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. N. Engl. J. Med., 320,88-93. 59 Hill, A., Melson, G.L., Clark, H.B. and Volpe, J.J. (1982): Hemorrhagic periventricular leukomalacia: diagnosis by real time ultrasound and correlation with autopsy findings. Pediatrics, 69, 282-284. 60 Hofmann-von Kap-herr, S. and Emmrich, P. (1979): Causes of postoperative deaths in gastroschisis and omphalocele. Prog. Pediatr. Surg., 13, 63-70. 61 Jellinger, K. and Seitelberger, F. (1971): Perivascular accumulation of lipids in the infant human brain. Acta Neuropathol., 19,331-342. 62 Joshi, A.K., Chen, C.I. and Tumell, R.W. (1987): Prevalence and significance of group B streptococcus in a large obstetric population. Can. Med. Assoc. J., 137,209-211. 63 Keller, M.S., DiPietro, M.A., Teele, R.L. et al. (1987): Periventricular cavitations in the first week of life. A.J.N.R., 8,291-295. 64 Kuhn, T.S. (1%2): The Structure of Scientific Revolutions. University of Chicago Press, Chicago. 65 Kundsin, R.B., Driscoll, S.G., Monson, R.R. et al. (1984): Association of Ureaplasma urealyticum in the placenta with perinatal morbidity and mortality. N. Engl. J. Med., 310,941-945. 66 Kundsin, R.B., Driscoll, S.G. and Pelletier, P.A. (1981): Ureaplasma ureaiyticum incriminated in perinatal morbidity and mortality. Science, 213,474-476. 67 Kupsky, W-J.. Kinney, H.C. and Lidov, H.G.W. (1989): Neuropathology of infants dying after extracorporeal membrane oxygenation (ECMO) (abstract). J. Neuropath. Exp. Neurol., 48,307. 68 Larroche, J.C. (1986): Fetal encephalopathies of circulatory origin. Biol. Neonate, 50,61-74. 69 Laub, M.C. (1986): increased periventricular echogenicity (periventricular halos) in neonatal brain: a sonographic study. Neuropediatrics, 17,39-43. 70 Levene, M.I., Wigglesworth, J.S. and Dubowitz, V. (1983): Hemorrhagic periventricular leukomalacia in the neonate: a real-time ultrasound study. Pediatrics, 71,794- 797. 71 Levene, M.I. (1988): Is neonatal cerebral ultrasound just for the voyeur? Arch. Dis. Child., 63, l72 Leviton, A., Gilles, F.H., Neff, R. and Yaney, P. (1976): Multivariate analysis of risk of perinatal telencephalic leucoencephalopathy. Am. J. Epidemiol., 104,621-626. 73 Leviton, A. and Gilles, F.H. (1984): Acquired perinatal leukoencephalopathy. Ann. Neurol., 16, I -8. 74 Leviton, A. and Gilles, F.H. (1974): Astrocytosis without globules in infant cerebral white matter. An epidemiologic study. J. Neurol. Sci., 22,329-340. 75 Leviton, A. and Gilles, F.H. (1983): Etiologic relationships among the perinatal telencephalic leucoencephalopathies. In: The Developing Human Brain. Growth and Epidemiologic Neuropathology, pp. 304-315. Editors: F.H. Giles, A. Leviton and E.C. Dooling. John Wright-PSG, Littleton, MA. 76 Leviton, A. and Gilles, F.H. (1971): Morphologic correlates of age at death of infants with perinatal telencephalic leucoencephalopathy. Am. J. Pathol., 65,303-309.

20 II

78

19 80 al a2 a3

a4 a5 86 a7 aa a9 90

91 92

93 94 95

% 91 98 99 100

Leviton, A. and Giles, F.H. (1984): Pre- and postnatal bacterial infections as risk factors of the perinatal leukoencephalopathies. In: Prevention of Physical and Mental Congenital Defects, Part B: Epidemiology, Early Detection and Therapy and Environmental Factors, pp. 7.5-19. Editor: M. Marois. Alan R. Liss, Inc., New York. Leviton, A. (1983): Autopsy data in epidemiologic studies. In: The Developing Human Brain: Growth and Epidemiologic Neuropathology, pp. 17-31. Editors: F.H. Gilles, A. Leviton and E.C. Dooling. Wright-PSG, Littleton, MA. Liggins, G.C., Kennedy, P.C. and Holm, L.W. (1967): Failure of initiation of parturition after electrocoagulation of the pituitary of the fetal lamb. Am. J. Obstet. Gynecol., 98, 1080. LOU, H.C., Lassen, N.A. and Frils-Hansen, B. (1979): Impaired autoregulation of cerebral blood flow in the distressed newborn infant. J. Pediatr., 94, 118. Lubran, M.M. (1988): Bacterial toxins. Ann. Clin. Lab. Sci., 18,58-71. McGregor, J.A., French, J.I., Lawellin, D. and Todd, J.K. (1988): Preterm birth and infection: pathogenic possibilities. Am. J. Reprod. Immunol. Microbial., 16,123-132. McGregor, J.A., French, J.I., Reller, L.B., Todd, J.K. and Makowski, E.L. (1986): Adjunctive erythromycin treatment for idiopathic preterm labor: results of a randomized, double-blinded, placebo-controlled trial. Am. J. Obstet. Gynecol., 154.98-103. McMenamin, J.R., Shackelford, G. and Volpe, J.J. (1984): Outcome of neonatal IVH with parenchymal echodense lesions. Ann. Neurol., 15,285-90. Mickel, H. and Gilles, F.H. (1970): Changes in glial cells during human telenphalic myelinogenesis. Brain, 93,337-346. Morrison, D.C., Duncan, R.L. Jr. and Goodman, S.A. (1985): In vivo biological activities of endotoxin. Prog. Clin. Biol. Res., 189,81-99. Nelson, K.B. and Ellenberg, J.H. (1985): Antecedents of cerebral palsy. I. Univariate analysis of risks. Am. J. Dis. Child., 139, 1031- 1038. Nelson, K.B. and Ellenberg, J.H. (1986): Antecedents of cerebral palsy: Multivariate analysis of risk. N. Engl. J. Med., 31581-86. Niswander, K.R. and Gordon, M. (1972): The Women and Their Pregnancies. W.B. Saunders, Philadelphia. Nowak, R.A., Samaras, S.E., Chorney, M.C., Hagen, D.R. and Dziuk, P.J. (1981): The effect of severing the spinal cord of fetal lambs on length of gestation. Am. J. Obstet. Gynecol., 157,464467. Nwasei, C.G., Pape, K.E., Martin, D.J., Becker, L.E. and Fitz, C.R. (1984): Periventricular infarction diagnosed by ultrasound: A postmortem correlation. J. Pediatr., 105, 106-l 10. Paneth, N., Rudelli, R. and Monte, W. (1990): White matter necrosis in very low birthweight infants: neuropathologic and ultrasonographic findings in 22 infants surviving six days or more. J. Pediatr., 116,975-984. Paneth, N. (1986): The etiology of cerebral palsy. Pediatr. Ann., 15, 191-201. Pape, K., Whyte, H., Martin, D. et al. (1985): Prognosis of grade IV intracerebral hemorrhage in the preterm infant. Pediatr. Res., 19,393A. Papile, L.A., Burstein, J., Burstein, R. et al. (1978): Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 gm. Pediatrics, 92,529-534. Papile, L.A., Musick-Bruno, G. and Schaefer, A. (1983): Relationship of cerebral IVH and early childhood neurologic handicaps. J. Pediatr., 103,273-277. Perlman, J.M., McMenamin, J.B. and Volpe, J.J. (1983): Fluctuating cerebral blood-flow velocity in respiratory distress syndrome. N. Engl. J. Med., 309,204. Perlman, J.M. and Volpe, J.J. (1987): Are venous circulatory abnormalities important in the pathogenesis of hemorrhagic and/or ischemic cerebral injury? Pediatrics, 80,705-711. Pinto, J., Paneth, N., Kazam, E. et al. (1988): Interobserver variability in neonatal cranial ultrasonography. Paediatr. Perinat. Epidemiol., 2,45-60. Pinto, J., Paneth, N., Rudelli, R. and Kairam, R. (1988): The neuropathological validation of cranial ultrasound diagnosis in low birthweight infants: some preliminary observations. In: Child

101 102 103 104 105 106

107 108 109

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White matter damage in preterm newborns--an epidemiologic perspective.

Prior to 1980, white matter abnormalities of the preterm newborn were known exclusively as pathological entities, but now cranial ultrasonography can ...
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