Brain injury in the premature infant--current concepts of pathogenesis and prevention.

Biol Neonate 1992:62:231-242

Department of Neurology. Children's Hospital, Boston, Mass., USA

Brain Injury in the Premature Infant - Current Concepts of Pathogenesis and Prevention

Keyw ords

Abstract

Premature infant Brain injury Pathogenesis Prevention

Brain injury in the premature infant and. particularly, the pre vention of that injury is an enormous problem. With modern neonatal intensive care, approximately 85% of very low birth weight infants survive, and of these survivals, approximately 5-15% exhibit major spastic motor deficit, grouped under the rubric, ‘cerebral palsy’, and an additional 25-50% exhibit less prominent developmental disabilities, particularly school fail ure.

The magnitude of the problem of brain injury in the premature infant and. particu larly, the prevention of that injury' is enor mous. Approximately 42,000 infants are born yearly in the United States with a birth weight < l,5 0 0 g . Approximately 85% of these in fants survive [1], and of the survivors, ap proximately 5-15% exhibit major spastic mo tor deficits, grouped under the rubric ‘cere bral palsy’, and an additional 25-50% exhibit less prominent developmental disabilities, particularly school failure [2-5], Moreover, data from Sweden [6] and England [7] dem onstrate that in recent years the prevalence of

cerebral palsy in infants with birth weight < 1,500 g has increased, probably largely sec ondary to the ever-increasing survival rates for these fragile small infants.

Major Neurological Manifestations and Neuropathology

The major neurological manifestations of brain injury in the premature infant are, firstly and uniformly, spastic motor deficits. The latter consist primarily of spastic quadriparesis, characteristically with greater affec-

Dr. Joseph J. Volpe, MD Neurologist in Chief Department of Neurology. Children’s Hospital 300 Longwood Avenue Boston, MA 02115 (USA)

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Joseph J. Volpe

Periventricular Leukomalacia

Periventricular leukomalacia refers to ne crosis of white matter in a characteristic dis tribution, i.e., the cerebral white matter dorsal and lateral to the external angle of the lateral ventricles [8]. Virchow [9] described the le sion over a century ago; several years later Parrot [10] noted that the injury often af fected the premature infant: approximately 60 years later Rydberg [11] suggested that the injury was related in some way to circulatory insufficiency at delivery, and in 1961 Schwartz [12] postulated that venous stasis caused by parturient events played a role in

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pathogenesis. The most lucid and complete description of periventricular leukomalacia is that of Banker and Larroche [ 13] who in 1962 described the characteristic topography of the lesion and its cellular characteristics and sug gested a relation to arterial border zones. Sub sequent work has refined further the patho genesis of periventricular leukomalacia (see below). Neuropathology The neuropathology of periventricular leu komalacia consists of focal necrosis of peri ventricular white matter, with a particular predilection for the periventricular tissue at the level of the optic radiation adjacent to the trigone of the lateral ventricles and at the level of the frontal cerebral white matter near the foramen of Monro [ 14], The incidence of such lesions in autopsy studies of premature in fants increases as a function of duration of postnatal survival and of frequency and sever ity of cardiorespiratory disturbances [14, 15]. In recent years the incidence in very low birth weight infants has been approximately 2540% [16-18], Less severe examples of periventricular leukomalacia consist of the appearance in the periventricular region of acutely damaged glial cells and astrocytosis [19], Gilles et al. [19] have used the term ‘perinatal telencephalic leukoencephalopathy’ to characterize this less severe neuropathology. A minority of examples of periventricular leukomalacia may be complicated by secondary hemor rhage [20], which usually takes the form of multiple petechial hemorrhages within the area of leukomalacia. We believe that this hemorrhagic periventricular leukomalacia should be distinguished from the periventric ular hemorrhagic infarction discussed below. Subsequently, with major degrees of periven tricular leukomalacia cystic cavities may de velop and with less severe degrees only di

Brain Injury in the Premature Infant


tion of lower than upper extremities (thus, the term ‘spastic diplegia’), and spastic hemiparesis. Intellectual deficits are not infrequent ac companiments. Less severe disturbances of motility and cognition occur, as noted above, in 25-50% of survivors. The major neuropathology for the spastic motor deficits, with or without accompanying intellectual deficits, are periventricular leukomalacia and periventricular hemorrhagic in farction (previously termed by us ‘hemor rhagic intracerebral involvement’) [8], (Other neuropathological substrates constitute some of the brain injury in the premature infant, e.g., posthemorrhagic hydrocephalus, pontosubicular necrosis, but on the basis of current data their roles appear to be small when com pared to the two neuropathological states un der discussion.) In the following we will con sider periventricular leukomalacia and peri ventricular hemorrhagic infarction in se quence in terms of the neuropathology, the means of identifying this pathology in vivo, the relation of this pathology to the subse quent neurological deficits noted above, the pathogenesis, the probable cause(s), and the possibilities for prevention.

Diagnosis in the Neonatal Period The two principal diagnostic procedures employed to identify periventricular leukomalacia in the living infant are ultrasound scan and CT scan. The former technique is preferable because of its high resolution, port able instrumentation, lack of ionizing radia tion, and relative lack of expense. On ultrasound scan, in the coronal projec tion the lesions appear as bilateral, primarily linear echodensities just adjacent to the ex ternal angles of the lateral ventricles [8], On parasagittal projections the echodensities may be diffusely distributed in periventricu lar white matter or localized to the sites of predilection for periventricular leukomalacia, i.e., the regions adjacent to the trigone of the lateral ventricles and/or adjacent to the ventricles at the level of the foramina of Monro. Interestingly, the pathological corre late of the echodensities has been primarily nonhemorrhagic periventricular leukomalacia [21,22], The characteristic evolution of the echodensities of periventricular leukomalacia is the formation of small cysts, often multiple (rendering a ‘Swiss cheese’ appearance) [21, 23, 24], Cyst formation occurs 2-3 weeks after the appearance of the echodensities. With relatively circumscribed cysts, it is com mon for the cystic lesions to disappear, at least ultrasonographically, after 1-3 months, leaving enlarged ventricles with decreased ce rebral myelin. It is notable, however, that in a recent cor relative ultrasonographic-neuropathological study, only 28% of periventricular white mat ter lesions were detected in vivo by ultraso nography [25]. The lesions missed were dif fuse astrocytic gliosis, ± myelin loss and/or focal necrosis [25]. The clinical correlate(s) of

these missed lesions are not known but likely to be appreciable. CT scan is a less preferable technique than ultrasonography to demonstrate periventricu lar leukomalacia because distinguishing in the newborn -lucencies in periventricular white matter that are indicative of periventricular leukomalacia from lucencies that are present in normal infants is difficult [26, 27], More over, CT requires transport of the sick infant and exposure to ionizing radiation. Neverthe less, the technique does demonstrate the le sions well, especially after several weeks when the degree of white matter atrophy can be assessed. Magnetic resonance imaging is of limited value in the neonatal period for diagnosis of periventricular leukomalacia not only be cause of the need for transport of the sick infant but because of the relatively long dura tion of the study and the difficulty of monitor ing the infant while in the scanner (because of the inability to use metallic monitoring de vices and to visualize the infant directly while in the magnet). However, magnetic resonance imaging effectively demonstrates the chronic pathological consequences of periventricular leukomalacia [28, 29]. Clinicopathological Correlations The major long-term clinical correlates of periventricular leukomalacia are spastic di plegia and, to a lesser extent, intellectual defi cits [8]. Spastic diplegia is a type of spastic quadriparesis in which lower extremities are affected more than upper extremities. Three major lines of evidence indicate that periven tricular leukomalacia results in spastic diple gia. First, the topography of the lesion in cludes the region of cerebral white matter traversed by descending fibers from motor cortex, and those fibers subserving function of lower extremities are more likely to be af fected by the periventricular locus of the ne

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minished cerebral myelin with dilated lateral ventricles.

Pathogenesis Pathogenesis of periventricular leukomalacia relates to three principal factors (table 1).

Table 1. P ath o g en esis o f p e riv e n tric u la r Icukom al-

acia 1 Periventricular vascular anatomic factors 2 Pressure-passive cerebral circulation 3 Enhanced vulnerability of actively differentiating and/or myelinating periventricular glial cells

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Firstly, certain periventricular vascular anatomic factors appear to render this region of the brain of the premature infant vulnera ble to cerebral ischemia. Thus, extending the basis observations of Van den Bcrgh and Vali der Eecken [30] and Van den Bergh [31], DeReuck [32, 33] and De Reuck et al. [34] have demonstrated the presence in the peri ventricular region of arterial border zones and end zones. These arterial border and end zones are essentially ‘distal fields’, i.e., wa tershed zones which would be expected to be most vulnerable to a fall in perfusion pressure and cerebral blood flow. Moreover. DeReuck [33] and Takashima and Tanaka [35] have shown that the border zones in periventricu lar white matter are most prominent in the least mature infants, because of the develop ment of the periventricular microvascular network. Additionally, it was shown that pre mature infants with periventricular leukomal acia and no obvious history of circulatory dis turbance were usually the most premature infants, whereas those infants with periven tricular leukomalacia and a history of circula tory disturbance more often were less prema ture infants. These data suggest that the de gree of ischemia required to produce periven tricular leukomalacia is dependent upon the state of development and is primarily a func tion of gestational age. At any rate, the arterial border zones and end zones in the periven tricular region have a characteristic distribu tion, and it is within these zones that periven tricular leukomalacia principally occurs. In deed, the most frequent loci for periventricu lar leukomalacia are within the two distinc tive anterior and posterior periventricular border zones (see Neuropathology). Secondly, a pressure-passive cerebral circu lation (table l) appears to exist in the pre mature infant, particularly the sick infant, and this phenomenon would render the infant susceptible to decreases in cerebral blood How



crosis. Second, the periventricular echodensities visualized by ultrasound in the neonatal period and shown to reflect periventricular leukomalacia by postmortem studies have been documented repeatedly by ourselves and others [23] to be followed by the development of spastic diplegia. Third, both periventricu lar leukomalacia and spastic diplegia have been known for many years to be characteris tic of the premature infant. The extent of the role of periventricular white matter injury in the genesis of intellec tual deficits is not entirely clear. Certainly infants with the largest lesions and marked spastic diplegia are often intellectually defi cient. It is noteworthy that the sites of predi lection for periventricular leukomalacia in clude fibers subserving association of visual, auditory and somesthelic functions, so criti cal for learning. Perhaps of major importance is the possibility that the relatively large pro portion of premature infants (see above) with less prominent developmental disabilities and school failure relates at least in part to the smaller degrees of injury to periventricular white matter that are so frequently missed by neonatal cranial ultrasonography (see above).

cate an enhanced vulnerability o f the actively differentiating and/or myelinating periventric ular glial cells (table I). Thus, experimental studies of neonatal animals have shown a lim ited increase in cerebral blood flow in the periventricular white matter, presumably be cause of limited vasodilatory capacity, to such potent stimuli as hypoxemia, hypercar dia and hypotension [43-46]. Moreover, when compared to other brain regions, the periventricular white matter of the neonatal (or fetal) animal subjected to hypoxic-isch emic insult exhibits a degree of active anaero bic glycolysis which exceeds substrate sup plies and leads to accumulation of lactic acid and depletion of high energy compounds in cerebral white matter [43-47], These latter two metabolic effects presumably occur be cause of the combination of the aforemen tioned limited vasodilatory capacity and the relatively active glycolytic capacity of peri ventricular glial cells. Finally, and perhaps related to the two factors just described, it is likely that the glial cells in periventricular white matter are intrinsically vulnerable to injury because they are in a developmental stage of active differentiation to astrocytes and to oligodendroglia. Moreover, some of the latter have begun active myelination in the perinatal period, and the distribution of hypoxic-ischemic periventricular white mat ter injury particularly includes areas of early myelinating activity [ 19], Probable Cause(s) and Prevention The discussion of pathogenesis above leads to the conclusion that periventricular leukomalacia is caused by systemic hypotension, sufficiently severe to lead to impaired cere bral blood flow. Thus, prevention will depend particularly on careful monitoring of circula tory failure, and prompt therapy of such fail ure. However, it is likely that in the most immature infants, because of periventricular

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and injury to periventricular white matter with hypotension. Thus, a linear direct rela tion between systolic blood pressure and cere bral blood flow, the latter measured by the 133Xc clearance technique [36], was docu mented in the first hours of life in a series of premature infants. With intact cerebrovascu lar autoregulation cerebral blood How should not be pressure-passive but rather should re main constant over a wide range of blood pressure, because of arteriolar constriction with elevations of blood pressure and arterio lar dilation with decreases of blood pressure. (Recent data suggest that clinically stable pre mature infants do not exhibit this pressurepassive cerebral circulation [37-39].) Experi mental and human studies [for a review, sec 8] suggest that the pressure-passive circula tory abnormality could result from: (1) the hypercardia or hypoxemia (or both) of perina tal asphyxia, respiratory disease and/or ‘nor mal’ vaginal delivery, (2) the cranial ‘trauma’ to the easily deformed premature head at the time o f ‘normal’ vaginal delivery, (3) an ‘im mature’ autoregulatory system related to the deficient muscularis of cerebral arterioles in the premature infant, (4) the occurrence of normal blood pressures that are dangerously close to the down slope of a normal autoregu latory curve, or (5) a combination of these fac tors. Whatever the mechanism(s), the clinical implications are enormous. Falls in arterial blood pressure may lead to seriously lowered cerebral blood flow and, ultimately, ischemic injury to vulnerable regions, such as the peri ventricular white matter. Decreases in sys temic blood pressure in the premature may result from such events as perinatal asphyxia, patent ductus arteriosus [40], myocardial fail ure, apneic spells with bradycardia [41], sep sis, and even simple handling with caretaking procedures [42], Thirdly, coupled with the pressure-passive circulatory disturbance are factors that indi

Periventricular Hemorrhagic Infarction

Periventricular hemorrhagic infarction re fers to hemorrhagic necrosis of periventricu lar white matter that is usually large and almost invariably asymmetric. The lesion most often coexists with intraventricular hemorrhage and. indeed, approximately 15% of all infants with intraventricular hemor rhage also exhibit periventricular hemor rhagic infarction [8], In contrast to periven tricular leukomalacia, this lesion does not have a long history in the medical literature and. in fact, we believe that its current promi nence relates to the recent increase in survival of very small premature infants. Neuropathology The neuropathology of periventricular hemorrhagic infarction is striking and con sists of a relatively large region of hemor rhagic necrosis in the periventricular white matter, just dorsal and lateral to the external angle of the lateral ventricle. The necrosis is strikingly asymmetric - in the largest series reported [48] 67% of such lesions were exclu sively unilateral and in virtually all of the remaining cases, grossly asymmetric, even though bilateral. Approximately one half of the lesions are extensive and involve the peri ventricular white matter from frontal to pa-

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rieto-occipital regions; the remainder arc more localized. Approximately 80% of cases are associated with large intraventricular hemorrhage, and commonly (and mistakenly) the parenchymal hemorrhagic lesion is de scribed as 'extension' of the hemorrhage. That simple extension of blood into cerebral white matter from germinal matrix or lateral ventri cle does not account for the periventricular hemorrhagic necrosis has been shown clearly by several ncuropathological studies [48-54], Microscopic study of this periventricular hemorrhagic necrosis indicates that the lesion is a hemorrhagic infarction [48. 49. 51-54], The careful studies of Gould et al. [53] and Takashima et al. [55] emphasize that (1) the hemorrhagic component consists usually of perivascular hemorrhages which follow closely the fan-shaped distribution of the me dullary veins in periventricular white matter, and that (2) the hemorrhagic component tends to be most concentrated near the ven tricular angle where these veins become con fluent and ultimately join the terminal vein in the subependymal region. Thus, it appears likely that periventricular hemorrhagic necro sis occurring in association with large intra ventricular hemorrhage is. in fact, a venous infarction. This lesion is distinguishable neuropathologieallv from secondary hemorrhage into periventricular leukomalacia. the isch emic, usually nonhemorrhagic, and symmet ric lesion of periventricular white matter of the premature infant (see above). However, distinction of these two lesions in vivo often is very difficult. In table 2 we compare the basic features of these two periventricular white matter lesions of the premature infant. Diagnosis in the Neonatal Period The two principal diagnostic procedures utilized to identify periventricular hemor rhagic infarction in vivo are ultrasound scan and CTscan. As noted for periventricular leu-

Brain Injury in (he Premature Infant


vascular factors related to maturation-depen dent deficiencies of the periventricular microcirculatory network (see above), periventricu lar leukomalacia may occur with systemic dis turbances so slight that they escape detection by even careful monitoring. Further delinea tion of pathogenesis, detection of imminent injury, and formulation of interventions to protect vulnerable periventricular tissue will be needed to prevent the entire spectrum of periventricular leukomalacia.

Table 2. Periventricular white matter lesions in the premature infant with intraventricular hemorrhage

Proposed designation

Markedly asymmetric

Grossly hemorrhagic

Probable site of circulatory disturbance

Periventricular leukomalacia

Uncommon

Uncommon

Arterial

Periventricular hemorrhagic infarction

Nearly invariable

Invariable

Venous

practical during the acute period, magnetic resonance imaging is particularly effective in demonstrating the extent of parenchymal de struction in the months following the neona tal period. Although not generally available, positron emission tomography and, specifically, the measurement of regional cerebral blood flow, thereby, has been utilized to show that the full extent of the white matter injury in periven tricular hemorrhagic infarction may be un derestimated by cranial ultrasonography [52], This underestimation presumably relates to the fact that the full extent of the infarction may not be hemorrhagic and, thus, may not be demonstrated unequivocally by ultrasound scan. Clinicopathological Correlations The major long-term correlates of periven tricular hemorrhagic infarction are spastic hemiparesis (or asymmetric quadriparesis) and intellectual deficits. The spastic hem ¡pa resis characteristically affects lower extremi ties as much as upper extremities, presumably because the periventricular locus of the lesion affects descending fibers from the lower ex tremity region. (This topography is different from the more laterally placed middle cere

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komalacia, ultrasonography is the preferred procedure. On ultrasound scan, in the coronal projec tion the lesions appear as unilateral or, if bilateral, clearly asymmetric, globular or triangular-shaped (‘fan-shaped’) echodensities radiating from the external angle of the lateral ventricle. On parasagittal projections the extent of the lesion is visualized best and may be classified as localized (i.e., involving only the frontal, parietal or parieto-occipital region) or extensive (extending from frontal to parieto-occipital regions). The characteristic ultrasonographic evolu tion of the large echodensities is to cyst forma tion, which, unlike the cysts of periventricular leukomalacia, tend to be single and large. Also unlike the cysts of periventricular leukomala cia. the cysts that form after periventricular hemorrhagic infarction rarely disappear over time. CT scan is a less preferable technique to demonstrate the acute lesion of periventricu lar hemorrhagic infarction for the reasons outlined regarding diagnosis of periventricu lar leukomalacia. However, the full extent of the periventricular parenchymal injury in the months after the acute period is delineated especially well by CT. Similarly, although not

Table 3. Outcome of premature infants with major IPE as a function of severity

Outcome

Severity ofIPEa extensive

localized

30/37(81)

14/38(37)

Major motor deficits

7/7(100)

12/15(80)

Cognitive < 80%b

6/7(85)

8/15(53)

Normal survivor1'

0/37 (0)

3/29(10)

Mortality

F igures in p a ren th eses in d ic a te percentage.

a Severity classified extensive if IPE extended from frontal to parieto-occipital regions and localized if IPE confined to the frontal, parietal or parieto-occipital region, as visualized on parasagittal ultrasound scan. b Cognitive function < 80% of average for age; psy chometric tests employed were different because they were chosen according to age and best abilities of the patient. c Surviving infant both free of motor deficit and cog nitive function > 80% of average.

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the topography of the IPE. and thus consisted of either spastic hemiparesis or asymmetric spastic quadriparesis. Prognostic estimation could be refined fur ther by considering the severity o f the IPE (ta ble 3). Thus, among infants with extensive IPE (i.e., IPE which included frontoparietooccipital regions), 30 of 37 (81 %) died, and of the 7 survivors, all had subsequent motor deficits. Overall, only 1 of the 37 infants with extensive IPE survived to have an IQ score greater than 80, and none was completely nor mal, i.e., free of motor deficit and IQ greater than 80. Among infants with localized IPE (i.e., IPE confined to either the frontal, parietal, or pa rieto-occipital regions) outcome was more fa vorable than after extensive IPE. Of the 38 infants with localized IPE, 14 (37%) died. Of the 15 survivors who could be followed subse quently, 3 were free of major motor deficit and 7 had psychometric test scores in excess of 80% of normal. Overall. 3 (10%) of the 29 infants with localized IPE and known out come had both normal motor and cognitive function subsequently. The subset of 8 infants with localized IPE that was unilateral had the most favorable cognitive outcome of all, i.e., only 1 had a psychometric test score less than 70% of normal. Pathogenesis The pathogenesis of the periventricular hemorrhagic necrosis that appears to be a venous infarction is not entirely established. However, a direct relation to germinal ma trix-intraventricular hemorrhage seems likely on the basis of three recently defined facts [48], First, approximately 80% of the paren chymal lesions were observed in association with large (and usually asymmetric) intraven tricular hemorrhage (table 4). Secondly, the parenchymal lesions invariably occurred on the same side as the larger amount of intra



bral artery infarct of the asphyxiated full-term infant, which results in affection of upper more than lower extremity.) The overall outcome of the largest reported series of infants with presumed periventricu lar hemorrhagic infarction, identified on ul trasound scan as intraparenchymal echodensity (IPE) greater than 1 cm, was unfavorable [48]. Thus, of the 75 infants studied, mortality rate was 59%. (This should be contrasted with a mortality rate of 8% in the same neonatal unit at the same time for infnats with the severest grade of intraventricular hemor rhage, i.e., grade III intraventricular hemor rhage, but no associated IPE.) Among the 22 survivors who could be examined on follow up, 86% exhibited major motor deficits and 64% had cognitive function less than 80% of normal. The motor deficits correlated with

komalacia. Thus, in such cases prevention would center around prevention of impaired cerebral blood flow, and thus, the measures described above in relation to causation and prevention of periventricular leukomalacia are relevant in this context.

Table 4. Association between occurrence of IPE and severity of intraventricular hemorrhage (IVH)

Severity of IVHa

Number with IPE

Grade III

58(77)

Grades I-II

13(18)

None

4(5)

Figures in parentheses indicate % of all patients with IPE. IPE was defined as periventricular intraparencymal echodensity > I cm in at least one dimension on ultrasound scan. 3 Severity graded I—III according to increasing amount of blood in lateral ventricles, as described pre viously [8].

Table 5. Relation of side of IPE with side of asym metric intraventricular hemorrhage (IVH)

Severity of IVH

IPE homolateral

IPE contralateral

Grade III

47

0

5

4

Grades I—II

Numbers refer to those patients with asymmetric IVH only. IPE homolateral = IPE on same side as larger amount of intraventricular blood; IPE contralat eral = IPE on opposite side of larger amount of intra ventricular blood.

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ventricular blood (table 5). Thirdly, the pa renchymal lesions developed and progressed after the occurrence of the intraventricular hemorrhage. The peak time of their occur rence was the 4th postnatal day [48], i.e., when 90% of cases of intraventricular hemor rhage have already occurred [8]. These data raised the possibility that the intraventricular hemorrhage and/or its associated germinal matrix hemorrhage led to obstruction of the terminal veins and hemorrhagic venous in farction. A similar conclusion has been sug gested from a recent neuropathological study [53]. Nevertheless, experimental studies raise the possibility that the intraventricular blood could contribute to the periventricular necro sis by causing impairment of periventricular blood flow secondary to increased intraven tricular pressure [56, 57] and/or local release of K+ from local release by red blood cells of lactic acid [58], or perhaps other vasoactive or otherwise injurious compounds. On balance, however, we consider most probable the pathogenetic notion of obstruction of medul lary and terminal veins by intraventricular and germinal matrix blood clot. Thus, the pathogenetic scheme seems to account for most examples of periventricular hemorrhagic infarction. This scheme should be distinguished from that operative for hem orrhagic periventricular lcukomalacia, al though clearly the lesions could coexist. The frequency of coexistence of the two lesions is not known. Additionally, the two pathoge netic schemes could operate in sequence, i.e.. periventricular leukomalacia could become hemorrhagic (and perhaps a larger area of injury) when germinal matrix or intraventric ular hemorrhage subsequently causes venous obstruction. As noted above, it is possible that a minor ity of cases of periventricular hemorrhagic infarction are leated to cerebral ischemia and the initial occurrence of periventricular leu-

Probable Cause(s) and Prevention The discussion of pathogenesis above leads to the conclusion that the major cause of peri ventricular hemorrhagic infarction is germi nal matrix-intraventricular hemorrhage. Thus, prevention of the infarction centers around prevention of the hemorrhage. Al though several approaches have been re ported to be at least partially effective for pre vention [8], we have favored the use of muscle paralysis [59].

Conclusions

There are two principal lesions that under lie the brain injury and the neurological mani festations thereof in the premature infant, i.c., periventricular leukomalacia and periventric ular hemorrhagic infarction. Both of these lesions may be largely preventable - periven tricular leukomalacia by preventing impaired cerebral blood flow, particularly secondary to systemic hypotension, and periventricular hemorrhagic infarction by preventing germi nal matrix-intraventricular hemorrhage.

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6 Hagberg B. Hagbcrg G. Olow I: The changing panorama of cerebral palsy in Sweden. Acta Paediatr Scand 1984:73:433-440. 7 Pharoah POD. Cooke T. Rosenbloom I, Cooke RWI: Trends in birth prevalence of cerebral palsy. Arch Dis Child 1987:62:379-384. ’ 8 Volpe JJ: Neurology of the New born. Philadelphia. Saunders, 1987, pp 160-280. 9 Virchow R: Zur pathologischen Anatomie des Gehirns. I Congéni tale Encephalitis and Myelitis. Vir chows Arch 1867:38:129—141. 10 Parrot J: Etude sur le ramollisse ment de l'encéphale chez le nouveau-né. Arch Physiol Norm Pathol 1873;5:59-75. 11 Rydberg E: Cerebral injury in new born children, consequent on birth trauma: With an inquiry into the normal and pathological anatomy of the neuroglia. Acta Pathol Micro biol Scand 1932:19S: 1-31. 12 Schwartz P: Birth Injuries of the Newborn: Morphology. Pathogene sis. Clinical Pathology and Pre vention. New York, Hafner. 1961. 13 Banker BQ, Larroche JC: Periven tricular leukomalacia of infancy. Arch Neurol 1962:7:32-50.

14 Shuman RM, Selednik LL: Periven tricular leukomalacia. A one-year autopsy study. Arch Neurol 1980: 37:231-239. ' 15 Barth PG, Stam FC. Oostcrkamp RF, Bezemcr PD. Koopman PA: On the relationship between germinal layer haemorrhage and telencephalic leucoencephalopathy in the pre term infant. Neuropaediatrie 1980; 11:17-24. 16 Pape KE, Armstrong DL, Fitzhardinge PM: Central nervous system pathology associated with mask ven tilation in the very low birthweight infant: A new etiology for intracerebellar hemorrhage. Pediatrics 1976: 58:473-481. 17 Skullerud K, Wcstrc B: Frequency and prognostic significance of ger minal matrix hemorrhage, periven tricular leukomalacia, and pontosubicular necrosis in preterm neo nates. Acta Neuropathol (Berl) 1986:70:257-261. 18 Larroche JC: Hypoxic brain damage in fetus and newborn. Morphologi cal characters. Pathogenesis. Pre vention. J Perinat Med 1982; 10(S)/2:29—3 1. 19 Gilles FH, Leviton A. Dooling EC: The Developing Human Brain: Growth and Epidemiologic Neuro pathology'. Boston. Wright. 1983.

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