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Prematurity, especially preterm birth (less than 32 weeks' gestation), is common and associated with high rates of both survival and neurodevelopmental disability, especially apparent in cognitive spheres. The neuropathological substrate of this disability is now recognized to be related to a variety of dysmaturational disturbances of the brain. These disturbances follow initial brain injury, particularly cerebral white matter injury, and involve many of the extraordinary array of developmental events active in cerebral white and gray matter structures during the premature period. This review delineates these developmental events and the dysmaturational disturbances that occur in premature infants. The cellular mechanisms involved in the genesis of the dysmaturation are emphasized, with particular focus on the preoligodendrocyte. A central role for the diffusely distributed activated microglia and reactive astrocytes in the dysmaturation is now apparent. As these dysmaturational cellular mechanisms appear to occur over a relatively long time window, interventions to prevent or ameliorate the dysmaturation, that is, neurorestorative interventions, seem possible. Such interventions include pharmacologic agents, especially erythropoietin, and particular attention has also been paid to such nutritional factors as quality and source of milk, breastfeeding, polyunsaturated fatty acids, iron, and zinc. Recent studies also suggest a potent role for interventions directed at various experiential factors in the neonatal period and infancy, i.e., provision of optimal auditory and visual exposures, minimization of pain and stress, and a variety of other means of environmental behavioral enrichment, in enhancing brain development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It has been widely suggested that brain damage in survivors of late preterm deliveries is similar to that in early preterm infants, only less severe. This report addresses this concept through reanalysis of published neuropathologic data obtained according to late preterm in comparison with early preterm ages. Findings suggest that the spectrum of brain injury in the late preterm infant, as determined in an autopsy population, is similar to that found in early preterm infants, with potential differential susceptibility for different neuronal, glial, and vascular indices. Further research is needed to more clearly define developmental cellular susceptibilities in preterm populations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Brain injury in the premature infant, a problem of enormous importance, is associated with a high risk of neurodevelopmental disability. The major type of injury involves cerebral white matter and the principal cellular target is the developing oligodendrocyte. The specific phase of the oligodendroglial lineage affected has been defined from study of both human brain and experimental models. This premyelinating cell (pre-OL) is vulnerable because of a series of maturation-dependent events. The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischemia and systemic infection/inflammation, both of which are common occurrences in premature infants. The focus of this review and of our research over the past 15-20 years has been the cellular and molecular bases for the maturation-dependent vulnerability of the pre-OL to the action of the two upstream mechanisms. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack. The work in both experimental models and human brain has identified a remarkable confluence of maturation-dependent factors that render the pre-OL so exquisitely vulnerable to these downstream mechanisms. Most importantly, elucidation of these factors has led to delineation of a series of potential therapeutic interventions, which in experimental models show marked protective properties. The critical next step, i.e., clinical trials in the living infant, is now on the horizon., (Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.)

The field of neonatal neurology, and specifically its focus on the premature infant, had its inception in neuropathologic studies. Since then, the development of advanced imaging techniques has guided our developing understanding of the etiology and nature of neonatal brain injury. This review promotes the concept that neonatal brain injury has serious and diverse effects on subsequent brain development, and that these effects likely are more important than simple tissue loss in determining neurologic outcome. Brain injury in the premature infant is best illustrative of this concept. This "encephalopathy of prematurity" is reviewed in the context of the remarkable array of developmental events actively proceeding during the last 16-20 weeks of human gestation. Recent insights into the brain abnormalities in survivors of preterm birth obtained by both advanced magnetic resonance imaging and neuropathologic techniques suggest that this encephalopathy is a complex amalgam of destructive and developmental disturbances. The interrelations between destructive and developmental mechanisms in the genesis of the encephalopathy are emphasized. In the future, advances in neonatal neurology will likely reiterate the dependence of this field on neuropathologic studies, including new cellular and molecular approaches in developmental neurobiology.

Brain abnormality in surviving premature infants is associated with an enormous amount of neurodevelopmental disability, manifested principally by cognitive, behavioral, attentional, and socialization deficits, most commonly with only relatively modest motor deficits. The most recognized contributing neuropathology is cerebral white matter injury. The thesis of this review is that acquired cerebellar abnormality is a relatively less recognized but likely important cause of neurodevelopmental disability in small premature infants. The cerebellar disease may be primarily destructive (eg, hemorrhage, infarction) or primarily underdevelopment. The latter appears to be especially common and relates to a particular vulnerability of the cerebellum of the small premature infant. Central to this vulnerability are the extraordinarily rapid and complex developmental events occurring in the cerebellum. The disturbance of development can be caused either by direct adverse effects on the cerebellum, especially the distinctive transient external granular layer, or by indirect remote trans-synaptic effects. This review describes the fascinating details of cerebellar development, with an emphasis on events in the premature period, the major types of cerebellar abnormality acquired during the premature period, their likely mechanisms of occurrence, and new insights into the relation of cerebellar disease in early life to subsequent cognitive/behavioral/attentional/socialization deficits.

Objective: The survival of very low birth weight infants has increased markedly in recent years. Unfortunately, the prevalence of significant and lifelong motor, cognitive, and behavioral dysfunction has remained a major problem confronting these children. The objective of this study was to perform screening tests for early autistic features in children with a history of very low birth weight and to identify risk factors associated with a positive screening result., Methods: We studied 91 ex-preterm infants < or = 1500 g at birth. Infants underwent conventional MRI studies at preterm and/or term-adjusted age. We collected pertinent demographic, prenatal, intrapartum, acute postnatal, and short-term outcome data for all infants. Follow-up assessments were performed at a mean age of 21.9 +/- 4.7 months, using the Modified Checklist for Autism in Toddlers, the Vineland Adaptive Behavior Scale, and the Child Behavior Checklist., Results: Twenty-six percent of ex-preterm infants had a positive result on the autism screening tool. Abnormal scores correlated highly with internalizing behavioral problems on the Child Behavior Checklist and socialization and communication deficits on the Vineland Scales. Lower birth weight, gestational age, male gender, chorioamnionitis, acute intrapartum hemorrhage, illness severity on admission, and abnormal MRI studies were significantly associated with an abnormal autism screening score., Conclusions: Early autistic behaviors seem to be an underrecognized feature of very low birth weight infants. The results from this study suggest that early screening for signs of autism may be warranted in this high-risk population followed by definitive autism testing in those with positive screening results.

Cerebral white matter injury, characterised by loss of premyelinating oligodendrocytes (pre-OLs), is the most common form of injury to the preterm brain and is associated with a high risk of neurodevelopmental impairment. The unique cerebrovascular anatomy and physiology of the premature baby underlies the exquisite sensitivity of white matter to the abnormal milieu of preterm extrauterine life, in particular ischaemia and inflammation. These two upstream mechanisms can coexist and amplify their effects, leading to activation of two principal downstream mechanisms: excitotoxicity and free radical attack. Upstream mechanisms trigger generation of reactive oxygen and nitrogen species. The pre-OL is intrinsically vulnerable to free radical attack due to immaturity of antioxidant enzyme systems and iron accumulation. Ischaemia and inflammation trigger glutamate receptor-mediated injury leading to maturation-dependent cell death and loss of cellular processes. This review looks at recent evidence for pathogenetic mechanisms in white matter injury with emphasis on targets for prevention and treatment of injury.

Objectives: Periventricular hemorrhagic infarction is a serious complication of germinal matrix-intraventricular hemorrhage in premature infants. Our objective was to determine the neurodevelopmental and adaptive outcomes of periventricular hemorrhagic infarction survivors and identify early cranial ultrasound predictors of adverse outcome., Methods: We retrospectively evaluated all cranial ultrasounds of 30 premature infants with periventricular hemorrhagic infarction and assigned a cranial ultrasound-based periventricular hemorrhagic infarction severity score (range: 0-3) on the basis of whether periventricular hemorrhagic infarction (1) involved > or = 2 territories, (2) was bilateral, or (3) caused midline shift. We then performed neuromotor, visual function, and developmental evaluations (Mullen Scales of Early Learning, Vineland Adaptive Behavior Scale). Developmental scores below 2 SD from the mean were defined as abnormal., Results: Median adjusted age at evaluation was 30 months (range: 12-66 months). Eighteen subjects (60%) had abnormal muscle tone, and 7 (26%) had visual field defects. Developmental delays involved gross motor (22 [73%]), fine motor (17 [59%]), visual receptive (13 [46%]), expressive language (11 [38%]), and cognitive (14 [50%]) domains. Impairment in daily living and socialization was documented in 10 (33%) and 6 (20%) infants, respectively. Higher cranial ultrasound-based periventricular hemorrhagic infarction severity scores predicted microcephaly and abnormalities in gross motor, visual receptive, and cognitive function., Conclusions: In the current era, two thirds of periventricular hemorrhagic infarction survivors develop significant cognitive and/or motor abnormalities, whereas adaptive skills are relatively spared. Higher cranial ultrasound-based periventricular hemorrhagic infarction severity scores predict worse outcome in several modalities and may prove to be a valuable tool for prognostication.

The aim of this study was to define the incidence, clinical associations, and short-term outcome of periventricular hemorrhagic infarction in the modern neonatal intensive care unit. From 5774 infants (birth weight<2500 gm), periventricular hemorrhagic infarction diagnosed by cranial ultrasound was identified and confirmed. gestational age-matched control infants were identified with normal cranial ultrasounds and detailed clinical data were obtained in both groups. Periventricular hemorrhagic infarction was confirmed in 58 infants. Incidence was 0.1% (1500-2500 gm), 2.2% (750-1500 gm), and 10% (<750 gm). Data across 6 study years reveal increased incidence in infants<750 gm. Compared with control infants, infants with periventricular hemorrhagic infarction had significantly greater association with assisted conception, intrapartum factors (emergency cesarean section, low Apgar scores), early neonatal complications (patent ductus arteriosus, pneumothorax, pulmonary hemorrhage), blood gas disturbances, and need for pressor, volume infusion, and respiratory support. Neonatal mortality of this group was 40% (n=23). Survivors had longer duration of mechanical ventilation and critical care stay compared with control subjects. Thirty-seven percent of survivors required cerebrospinal fluid shunt placement. Periventricular hemorrhagic infarction remains an important neurologic complication of prematurity. A growing population of survivors is apparent among infants with birth weight<750 gm. Multiple hemodynamic factors associated with periventricular hemorrhagic infarction cluster in the intrapartum and early neonatal periods.

Objective: Early diagnosis of periventricular hemorrhagic infarction in premature infants is based on bedside neonatal cranial ultrasonography. Currently, evaluation of its morphology and evolution by cranial ultrasound relies largely on data predating major advances in perinatal care and lacks a consistent classification system for determining severity of injury. The objective of this study was to examine the ultrasonographic morphology and evolution of periventricular hemorrhagic infarction in the modern NICU and to determine the value of a cranial ultrasonography-based severity score for predicting outcome., Methods: We retrospectively evaluated all cranial ultrasounds and medical records of 58 premature infants with periventricular hemorrhagic infarction. We assigned each subject a severity score based on extent of echodensity, unilateral versus bilateral, and presence or absence of midline shift. A neurologic examination was performed after 12 months adjusted age., Results: The parenchymal echodensity of periventricular hemorrhagic infarction most often involved parietal and frontal territories and evolved into single and/or multiple cysts. One quarter of cases were bilateral, and nearly 70% were extensive. Higher severity scores were significantly associated with pulmonary hemorrhage and low bicarbonate levels and with outcomes of fatality, early neonatal seizures, and motor disability., Conclusions: Despite advances in perinatal medicine, periventricular hemorrhagic infarction remains an important complication of prematurity. Periventricular hemorrhagic infarction can be graded using a scoring system based on sonographic characteristics. Higher severity scores predict worse outcome. Such severity scoring could improve the clinician's ability to counsel parents regarding management decisions and early intervention strategies.

Background: Advanced neuroimaging techniques have brought increasing recognition of cerebellar injury among premature infants. The developmental relationship between early brain injury and effects on the cerebrum and cerebellum remains unclear., Objectives: To examine whether cerebral parenchymal brain lesions among preterm infants are associated with subsequent decreases in cerebellar volume and, conversely, whether primary cerebellar injury is associated with decreased cerebral brain volumes, with advanced, 3-dimensional, volumetric MRI at term gestational age equivalent., Methods: Total cerebellar volumes and cerebellar gray and myelinated white matter volumes were determined through manual outlining for 74 preterm infants with unilateral periventricular hemorrhagic infarction (14 infants), bilateral diffuse periventricular leukomalacia (20 infants), cerebellar hemorrhage (10 infants), or normal term gestational age equivalent MRI findings (30 infants). Total brain and right/left cerebral and cerebellar hemispheric volumes were calculated., Results: Unilateral cerebral brain injury was associated with significantly decreased volume of the contralateral cerebellar hemisphere. Conversely, unilateral primary cerebellar injury was associated with a contralateral decrease in supratentorial brain volume. Cerebellar gray matter and myelinated white matter volumes were reduced significantly not only among preterm infants with primary cerebellar hemorrhage but also among infants with cerebral parenchymal brain injury., Conclusions: These data suggest strongly that both reduction in contralateral cerebellar volume with unilateral cerebral parenchymal injury and reduction in total cerebellar volume with bilateral cerebral lesions are related to trophic transsynaptic effects. Early-life cerebellar injury may contribute importantly to the high rates of cognitive, behavioral, and motor deficits reported for premature infants.

Unlabelled: Cerebellar hemorrhage (CBH) in premature infants is increasingly diagnosed secondary to improved neuroimaging techniques and survival of very small preterm infants. Information is limited, however, on the incidence, topography, and risk factors for CBH in the preterm infant., Objectives: To define the incidence of CBH in preterm infants diagnosed by neonatal cranial ultrasound (US), describe the sonographic features of CBH, and identify maternal and perinatal risk factors associated with this lesion., Methods: A systematic electronic database search identified preterm infants born 1998-2002 with US diagnosis of CBH. For 35 cases of CBH we double-matched (according to gestational age, gender, and year of birth) 70 preterm controls with normal cranial USs and performed detailed medical-record reviews for both patients and controls., Results: Unilateral CBH was seen in 25 patients (71%), vermian hemorrhage was seen in 7 (20%), and combined bihemispheric and vermian hemorrhage was seen in 3 (9%). Isolated CBH occurred in 8 patients (23%); the remaining infants had associated supratentorial lesions. The incidence of CBH in preterm infants weighing <750 g at birth showed significant increase over the study period. Univariate analyses identified maternal, intrapartum, and early postnatal hemodynamic risk factors; multivariate regressions indicated that emergent caesarian section, patent ductus arteriosus, and lower 5-day minimum pH independently increased the odds of CBH. Neonatal mortality and morbidity were significantly higher among patients with CBH compared with preterm controls., Conclusions: CBH is an important complication of extreme preterm birth and has been underrecognized in surviving preterm infants. Predictors of CBH seem to be multifactorial and include combined maternal, intrapartum, and early postnatal factors.

Objectives: The aim of this study was to define qualitatively the nature and extent of white and gray matter abnormalities in a longitudinal population-based study of infants with very low birth weight. Perinatal factors were then related to the presence and severity of magnetic resonance imaging (MRI) abnormalities., Methods: From November 1998 to December 2000, 100 consecutive premature infants admitted to the neonatal intensive care unit at Christchurch Women's Hospital were recruited (98% eligible) after informed parental consent to undergo an MRI scan at term equivalent. The scans were analyzed by a single neuroradiologist experienced in pediatric MRI, with a second independent scoring of the MRI using a combination of criteria for white matter (cysts, signal abnormality, loss of volume, ventriculomegaly, corpus callosal thinning, myelination) and gray matter (gray matter signal abnormality, gyration, subarachnoid space). Results were analyzed against individual item scores as well as the presence of moderate-severe white matter score, total gray matter score, and total brain score., Results: The mean gestational age was 27.9+/-2.4 weeks (range, 23-32 weeks), and mean birth weight was 1063+/-292 g. The greatest univariate predictors for moderate-severe white matter abnormality were lower gestational age (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.7; P<.01), maternal fever (OR, 2.2; 95% CI, 1.1-4.6; P<.04), proven sepsis in the infant at delivery (OR, 1.8; 95% CI, 1.1-3.6; P=0.03), inotropic support (OR, 2.7; 95% CI, 1.5-4.5; P<.001), patent ductus arteriosus (OR, 2.2; 95% CI, 1.2-3.8; P=.01), grade III/IV intraventricular hemorrhage (P=.015), and the occurrence of a pneumothorax (P=.05). There was a significant protective effect of intrauterine growth restriction (OR, 0.51; 95% CI, 0.23-0.99; P=.04). Gray matter abnormality was highly related to the presence and severity of white matter abnormality. A unique pattern of cerebral abnormality consisting of significant diffuse white matter atrophy, ventriculomegaly, immature gyral development, and enlarged subarachnoid space was found in 10 of 11 infants with birth gestation <26 weeks. Given the later outcome of these infants, this pattern may have very high risk for later global neurodevelopmental disability., Conclusions: This MRI study confirms a high incidence of cerebral white matter abnormality at term in an unselected population of premature infants, which is predominantly a result of noncystic injury in the extremely immature infant. We confirm that the major perinatal risk factors for white matter abnormality are related to perinatal infection, particularly maternal fever and infant sepsis, and hypotension with inotrope use. We have defined a distinct pattern of diffuse white and gray matter abnormality in the extremely immature infant.

Objective: Current methods for early identification of cerebral white matter injury in the premature infant at the bedside are inadequate. This study investigated the utility of advanced spectral analysis of the neonatal electroencephalogram (EEG) in the early diagnosis of white matter injury in the premature infant. The critical measurement used, suggested largely by previous studies in animal models, was the spectral edge frequency (SEF), calculated here as the frequency below which 90% of the power in the EEG exists., Methods: Fifty-nine very low birth weight infants (87% of eligible infants) had electrodes placed over the central and parietal regions (C3, P3, C4, and P4 sites according to the 10-20 international system) for the collection of EEG amplitude, intensity, and SEF. All averaged signals were analyzed off-line using software (Chart Analyzer; BrainZ Instruments, Auckland, NZ). All infants had a magnetic resonance imaging scan at term to identify the presence and severity of white matter injury., Results: There was no significant difference between conventional EEG amplitude and intensity for infants with or without evidence of white matter injury. However, premature infants with increasingly severe white matter injury had progressively lower SEFs compared with infants who did not exhibit white matter injury., Conclusions: These data suggest that SEF-based measures are useful for defining the presence and severity of white matter injury at the bedside.

Major advances in understanding the cellular mechanisms of brain injury have presented a host of potential targets for intervention. This is particularly true of hypoxic-ischemic injury, the most important form of perinatal brain injury. As the window for effective clinical intervention may be particularly narrow in the fetus and newborn because of the often-delayed and subtle presentation of the onset of the insult, recent focus has been on defining and countering the more delayed mechanisms of brain injury. Recent insights into the mechanisms of oligodendrocyte injury and the role of inflammatory substances in perinatal brain injury are also discussed.

Objective: The purpose of this study was to compare both the volumes of the lateral ventricles and the cerebral white matter with gestational age at birth of children with periventricular white matter (PVWM) T2-signal hyperintensities on MR images. The spectrum of neuromotor abnormalities associated with these hyperintensities was also determined., Materials and Methods: We retrospectively reviewed the MR images of 70 patients who were between the ages of 1 and 5 years and whose images showed PVWM T2-signal hyperintensities. The patients were divided into premature (n = 35 children) and term (n = 35) groups depending on their gestational age at birth. Volumetric analysis was performed on four standardized axial sections using T2-weighted images. Volumes of interest were digitized on the basis of gray-scale densities of signal intensities to define the hemispheric cerebral white matter and lateral ventricles. Age-adjusted comparisons of volumetric measurements between the premature and term groups were performed using analysis of covariance., Results: The volume of the cerebral white matter was smaller in the premature group (54 +/- 2 cm(3)) than in the term group (79 +/- 3 cm(3), p < 0.0001). The volume of the lateral ventricles was greater among the patients in the premature group (30 +/- 2 cm(3)) than among those in the term group (13 +/- 1 cm(3), p < 0.0001). Fifty percent of all the premature children had spastic diplegia or quadriplegia. Thirty-two percent of all the term children had hypotonia. There were patients in both groups whose PVWM T2-signal hyperintensities did not correlate with any neuromotor abnormalities but were associated with seizures or developmental delays., Conclusion: The differences in volumetric measurements of cerebral white matter and lateral ventricles in children with PVWM T2-signal hyperintensities are related to their gestational age at birth. Several neurologic motor abnormalities are found in children with such hyperintensities.

Line scan diffusion tensor magenetic resonance imaging (DT-MRI) of the cervical spinal cord was demonstrated in vivo for unsedated preterm (gestational age 24-30 weeks at birth), very low birthweight (birthweight 620-1300 g) infants at postmenstrual ages from 29-40 weeks. Scalar invariant measures of diffusion [apparent diffusion coefficient (ADC) and relative anisotropy (RA)] determined from a cervical cord region of interest in each case are reported, characterizing the maturational status of the normal third trimester and newborn spinal cord. Mean ADC of 11 infants was 1.2 +/- 0.1 microm(2)/msec and the mean RA was 24.3 +/- 4.9%. Normal infant cord neural fiber tract morphology was visualized using a mapping of the predominant diffusion tensor eigenvector. Potential clinical applications of line scan DT-MRI of the spinal cord of preterm and term newborns for assessment of spinal cord injury are discussed. J. Magn. Reson. Imaging 2001;13:949-953., (Copyright 2001 Wiley-Liss, Inc.)

Objective: The specific aim of this study was to quantify at term the influence of postnatal systemic dexamethasone treatment for neonatal chronic lung disease on subsequent brain growth and development in premature infants without evidence of severe intraventricular hemorrhage or white matter injury., Methods: Eighteen premature (23 to 31 weeks) infants, 7 treated with dexamethasone and 11 not treated, were studied at term, ie, 38 to 41 postconceptional weeks, by an advanced quantitative volumetric 3-dimensional magnetic resonance imaging (MRI) technique to quantify cerebral tissue volumes. Fourteen healthy term infants also were studied for comparison. A sequence of image processing algorithms was used to segment each of the MRI slices into the following separate tissue classes: cerebral cortical gray matter, basal ganglia/thalami, unmyelinated white matter, myelinated white matter, and cerebrospinal fluid, all classified based on magnetic resonance signal intensity and anatomic location. A final summing of voxels for each tissue class was performed to compute absolute volumes in milliliters., Results: Cerebral cortical gray matter volume in premature infants treated with dexamethasone was reduced 35% when compared with gray matter volume in premature infants not treated with dexamethasone (mean +/- standard deviation, 130.3 +/- 54.0 vs 200.6 +/- 35.1 mL, respectively). Subcortical gray matter volumes (basal ganglia and thalami) and myelinated and unmyelinated white matter volumes were not significantly different among the treated and untreated groups. However, premature infants treated with dexamethasone exhibited a reduction (30%) in total cerebral tissue volume compared with total cerebral tissue volume in both the premature infants not treated with dexamethasone and the control term infants (312.7 +/- 43.7 vs 448.2 +/- 50.2 and 471.6 +/- 36.4 mL respectively). This latter finding relates primarily to the decrease in cerebral cortical gray matter volume., Conclusions: The data suggest an impairment in brain growth, principally affecting cerebral cortical gray matter, secondary to systemic dexamethasone therapy. Although the premature infants who received dexamethasone were smaller with more severe respiratory disease, these findings are consistent with growing evidence of a potential deleterious effect of dexamethasone on neonatal brain and subsequent neurodevelopmental outcome. This apparent deleterious effect should be taken into consideration by clinicians when weighing the potential risks and benefits of this therapy for low birth weight infants with neonatal chronic lung disease.

There are two principal lesions that underlie brain injury and the neurologic manifestations in the premature infant: periventricular hemorrhagic infarction and periventricular leukomalacia. Both of these lesions may be potentially preventable: periventricular hemorrhagic infarction by preventing germinal matrix-IVH, and periventricular leukomalacia by detecting impaired cerebrovascular regulation with near-infrared spectroscopy, preventing the impaired cerebral blood flow and interrupting the cascade to oligodendroglial cell death, perhaps by such agents as free-radical scavengers. Prenatal magnesium sulfate also may be valuable. The greatest progress toward prevention has been made regarding periventricular hemorrhagic infarction, but the advent of new technologies, especially near-infrared spectroscopy, and of new insights into the cellular basis for oligodendroglial vulnerability provide hope for prevention of periventricular leukomalacia.

This report describes the occurrence of rapid progression of hydrocephalus after discharge from the nursery in four of 48 infants who had had previous arrest of progression of post-hemorrhagic hydrocephalus, and at least partial resolution of ventriculomegaly. This later-onset hydrocephalus occurred at a mean age of seven months; the most consistent presenting clinical feature was rapid head growth. Three of the four infants required a ventriculo-peritoneal shunt and the fourth was treated with acetazolamide, with apparent resolution of the hydrocephalus. Newborn infants with post-hemorrhagic hydrocephalus should be followed carefully throughout the first year for prompt detection of later hydrocephalus.

Nineteen premature infants with progressive posthemorrhagic hydrocephalus with increased intracranial pressure were treated with external ventricular drainage. Progression of hydrocephalus was arrested during the drainage period in each patient. Three of the 19 infants required no further therapy. Sixteen had recurrence of progressive ventricular dilatation, and all but one eventually had placement of a ventriculoperitoneal shunt, although under more favorable medical conditions than existed at the time of institution of external ventricular drainage. Three of the 19 infants died of causes unrelated to the external ventricular drainage. Of the 16 survivors, seven infants had a developmental quotient or formal IQ of over 75. Outcome was poorest for those infants with accompanying intracerebral hemorrhage. We consider ventriculostomy to be an effective temporizing measure in small infants with rapidly progressive posthemorrhagic hydrocephalus with increased intracranial pressure in whom ventricular decompression is necessary and placement of a ventriculoperitoneal shunt is not feasible.

Ventricular dilation is common following intraventricular hemorrhage. Neuropathologic studies have demonstrated that chronic posthemorrhagic hydrocephalus most commonly is a result of an obliterative arachnoiditis in the posterior fossa or is due to obstruction of flow of CSF within the ventricular system. Recent use of ultrasound scanning has demonstrated the occurrence of ventricular dilation within days of intraventricular hemorrhage (prior to the expected time of development of arachnoiditis). In the case described, serial real-time ultrasound scans demonstrated small mobile particles within dilated ventricles seven days following intraventricular hemorrhage. There was no obstruction of CSF flow within the ventricular system. Thus, in this case, ventricular dilation may have been secondary to plugging of arachnoid villi by the small particulate matter and, as a consequence, decrease in CSF reabsorption.

This article reviews the pathophysiology of PV-IVH, the clinical aspects, the means of establishing the diagnosis, and the problem of posthemorrhagic ventricular dilation. The most recent advances are emphasized.

Diagnosis of periventricular-intraventricular hemorrhage (IVH) and its neuropathological consequences and accompaniments in the living infant has been facilitated greatly by the introduction of real-time cranial ultrasonography. The major advantages of the technique include high-resolution capability, portable instrumentation, lack of ionizing radiation, and relative affordability. Prognosis in infants with IVH relates to the mechanisms of brain injury, the most important of which are prior hypoxic-ischemic insults, posthemorrhagic hydrocephalus, and periventricular hemorrhagic infarction. The last of these is most critical and it is now clear that careful quantitative assessment of the ultrasonographic appearance of the periventricular parenchyma in the infant with IVH during the acute period of illness is of major value in estimating outcome. Prevention of IVH remains the most important goal. Prenatal interventions include prevention of premature birth (currently a very elusive goal in the United States), transportation of the premature infant to a tertiary facility in utero rather than after birth (an approach of proven value), prenatal administration of phenobarbital or vitamin K (initially promising data that require confirmation and amplification), and optimal management of labor and delivery. Postnatal interventions include careful resuscitation of newborns, correction of fluctuating cerebral blood flow velocity, correction or prevention of other major hemodynamic disturbances, and correction of abnormalities of coagulation. Of these interventions the use of muscle paralysis to correct fluctuating cerebral blood flow velocity has shown the most striking benefit vis-à-vis prevention of IVH. Postnatal pharmacological interventions that have been studied in detail include the use of phenobarbital, indomethacin, ethamsylate, and vitamin E. No single agent among this group has been shown consistently to lead to a decrease in incidence and severity of IVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Of all patients with intraventricular hemorrhage, those with hemorrhagic intracerebral involvement exhibit the highest rates of mortality and neurologic morbidity and, indeed, account for the vast majority of all neurologic impairment in infants with intraventricular hemorrhage. Insight into the basic nature of the critical cerebral involvement requires determination of regional cerebral blood flow, previously not possible. Positron emission tomography (PET) now provides the capability of measuring regional cerebral blood flow with high resolution and little risk. In this study, we utilized PET in six premature infants (920 to 1,200 g) with major intraventricular hemorrhage and hemorrhagic intracerebral involvement to measure regional cerebral blood flow during the acute period (5 to 17 days of age). Cerebral blood flow was determined after intravenous injection of H2O, labeled with the positron-emitting isotope, 15O (oxygen 15). Findings were similar and dramatic in all six infants. In the area of hemorrhagic intracerebral involvement, little or no cerebral blood flow was detected. However, in addition, surprisingly, a marked two- to fourfold reduction in cerebral blood flow was observed throughout the affected hemisphere, well posterior and lateral to the intracerebral hematoma, including cerebral white matter and, to a lesser extent, frontal, temporal, and parietal cortex. In the one infant studied a second time, ie, at 3 months of age, the extent and severity of the decreased cerebral blood flows in the affected hemisphere were similar to those observed on the study during the neonatal period. At the three autopsies, the affected left hemisphere showed extensive infarction, corroborating the PET scans. These observations, the first demonstration of the use of PET in the determination of regional cerebral blood flow in the newborn, show marked impairments in regional cerebral blood flow in the hemisphere containing an apparently restricted intracerebral hematoma, indicating that the hemorrhagic intracerebral involvement is only a component of a much larger lesion, ischemic in basic nature, ie, an infarction. This large ischemic lesion explains the poor neurologic outcome in infants with intraventricular hemorrhage and hemorrhagic intracerebral involvement.

Controversy exists concerning the degree of importance of periventricular intraparenchymal echodensities (IPE) observed on neonatal ultrasound scans in the determination of subsequent neurologic disability in premature infants. In this report, IPE was studied in 75 infants weighing less than 2,000 g at birth to determine the basic characteristics of the lesion, the likely pathogenesis, the outcome, and the aspects of the ultrasonographic appearance in the acute period of neonatal illness that are important for prediction of outcome. IPE was defined as any periventricular echodensity greater than 1 cm in at least one dimension. IPE was strikingly associated with large areas of intraventricular hemorrhage (IVH) (81% of cases). IPE was distinctly asymmetric. Thus, the lesion was either exclusively unilateral (67%) or bilateral with marked predominance on one side. The associated IVH was asymmetric in approximately 80% of cases, and in all 50 cases of large asymmetric IVH, IPE occurred on the same side as the larger amount of intraventricular blood. Moreover, more than 50% of such cases of IPE associated with large asymmetric IVH were progressive. Neuropathologic correlation showed that IPE represented hemorrhagic necrosis of periventricular tissue. Concerning pathogenesis, these data raise the possibility that large asymmetric IVH is related etiologically to IPE. Outcome varied with the severity of the IPE. Thus, the mortality rate among the 38 infants with extensive IPE was 79%. Of the survivors with extensive IPE, all had subsequent major motor deficits and all but one exhibited cognitive function less than 80% of normal. Among the 37 infants with localized IPE, the mortality rate was 38%. Of the survivors, although 79% had major motor deficits, 43% had cognitive function greater than 80% of normal. Thus, the findings demonstrate that with extensive IPE there is little or no chance for survival with normal neurologic and cognitive outcome, but with localized IPE, although major motor deficits are common, an appreciable proportion of infants have cognitive function in the normal range. Careful, quantitative assessment of the ultrasonographic features of IPE in the acute period of illness in the premature infant is of major value in estimating outcome.

In two thirds of the premature infants who survived large periventricular intracerebral hemorrhage, a porencephalic cyst developed at the site of parenchymal hemorrhage. The porencephaly seems to develop as a result of local parenchymal destruction by the hemorrhage itself. These cysts can occur in the absence of posthemorrhagic hydrocephalus or increased intracranial pressure. Three of four infants who were observed for at least five months had lateralized motor deficit that corresponded to the cyst.

The incidence, timing, severity, and outcome of intraventricular hemorrhage (IVH) were studied in extremely small premature infants with birth weights (BWs) between 500 and 700 g; 366 infants with BWs between 701 and 1500 g, admitted during the same period, served as a comparison group. Intraventricular hemorrhage occurred in 34 (62%) of 55 infants with BWs less than 700 g vs 91 (25%) of the 366 comparison infants. In the group with BWs less than 700 g, IVH occurred in the first 18 hours, from 19 to 72 hours, and after 72 hours of life in 62%, 20%, and 18% of the infants, respectively. In the comparison group, the occurrence for these periods was 13%, 82%, and 5%, respectively. The severity of IVH in infants with BWs less than 700 g was grade III (with or without intraparenchymal hemorrhage) in 97% of the lesions, but in the comparison group such severe IVH accounted for only 32% of the lesions. Intraventricular hemorrhage was a common contributor to death in the infants with BWs less than 700 g. Thus, in 24 infants who died before 72 hours of life, 21 infants (88%) had severe IVH. In addition, intracranial hemorrhage (four infants with IVH and two infants with intracerebellar hemorrhage) occurred late (days 8 to 25) and contributed to death in six of the infants with BWs less than 700 g. These data indicate that in comparison with larger premature infants, infants with BWs less than 700 g exhibit a higher incidence of IVH, which is more severe, occurs earlier, and is associated more often with a fatal outcome. In addition, late and lethal intracranial hemorrhage is also more likely to occur in these smaller infants.

The effect of episodes of apnea with bradycardia on cerebral circulation was studied during 101 episodes in 15 premature infants. The objectives of the study were to determine whether important alterations occur in cerebral hemodynamics with apnea and bradycardia and whether such alterations relate to systemic hemodynamic events. The transcutaneous Doppler technique was used to measure blood flow velocity in the anterior cerebral arteries. With episodes of apnea complicated by mild-to-moderate bradycardia (heart rate less than 120 or greater than 80), a decrease in diastolic flow velocity was noted with little or no change in systolic flow velocity. With episodes complicated by severe bradycardia (heart rate less than 80), the diastolic flow velocity fell to the electronic base line, and a progressive decrease in systolic flow velocity also was observed. Accompanying the changes in cerebral blood flow velocity were similar changes in arterial blood pressure. These data suggest potential deleterious hypoxic-ischemic effects on brain from apnea with severe bradycardia in the preterm infant.

The relationship of pneumothorax to the occurrence of intraventricular hemorrhage (IVH) has been studied in the premature newborn. The major objective of the study was to determine whether the systemic hemodynamic changes that occur with pneumothorax are reflected in the cerebral circulation and whether these changes play a role in pathogenesis of IVH. Blood flow velocity was measured in the anterior cerebral arteries by a transcutaneous Doppler technique in nine infants who developed pneumothorax in the first 3 days of life. At the time of pneumothorax there was a marked increase in flow velocity, especially during diastole, and, with resolution of pneumothorax, flow velocity returned to normal levels over the ensuing hours. The changes in flow velocity correlated closely with systemic hemodynamic changes that occurred with pneumothorax, ie, and increase in mean systemic blood pressure, especially diastolic pressure. IVH, documented by serial ultrasound scans, was observed shortly after pneumothorax in the nine infants. The data thus demonstrate a marked increase in flow velocity in the cerebral circulation at the time of pneumothorax. This increase is of importance in the genesis of IVH as is suggested further by the occurrence of IVH soon after the cerebral hemodynamic changes.

Marked changes in blood flow velocity in the anterior cerebral arteries, measured by a Doppler technique, have been related to PDA in premature infants. Thus, 55 premature infants of birth weight less than 2,000 gm were studied. Ten developed PDA between days three and ten of life. A sharp decrease in diastolic flow velocity and an increase in pulse amplitude in the ACA was observed with the occurrence of PDA. Return of these values to normal occurred promptly following closure of the lesion. These changes in flow velocity and pulse amplitude in the ACA appear to be determined principally by changes in systemic diastolic pressure which accompany PDA. There was no consistent relationship between the changes in flow velocity and arterial PCO2 values. These data suggest that PDA may be involved in the genesis of ischemic and hemorrhagic cerebral injury in the premature newborn infant. Thus, the decrease in flow velocity appears to represent a "steal" of blood from the cerebral arteries, analogous to other documented steal phenomena observed in older patients. Major fluctuations of blood flow velocity in the ACA, with opening and closure of the PDA, and the increase in amplitude of each pulse with PDA may, in the presence of disturbed autoregulation, cause rupture of the capillaries of the germinal matrix and thus, IVH.

Intraventricular hemorrhage of the premature infant originates in the subependymal germinal matrix. Important neuropathological complications of the hemorrhage are post-hemorrhagic hydrocephalus and periventricular hemorrhagic infarction. The latter infarction and the ischemic lesion, periventricular leukomalacia, are the most important forms of brain injury in the premature infant. Pathogenesis of intraventricular hemorrhage relates to intravascular, vascular, and extravascular factors.

This article reviews the significance of hypoxic-ischemic encephalopathy and the associated patterns of cerebral injury in the context of the most probable timing of the insult and prognosis. The evolution of the clinical features of significant hypoxic-ischemic encephalopathy, and the diagnostic value of imaging and electrophysiologic and metabolic studies are discussed. Current approaches to management are outlined.

The relationship of neonatal seizures to changes in the cerebral circulation was studied in 12 premature newborn infants. The objectives of the study were to determine whether important alterations in cerebral hemodynamics occur with neonatal seizures and whether such alterations relate to systemic hemodynamic events. Blood flow velocity in the anterior cerebral arteries was measured by a transcutaneous Doppler technique. A marked increase in cerebral blood flow velocity was documented with seizures in every patient. The prominent changes in the cerebral circulation occurred despite the fact that 10 of the 12 infants had only subtle seizures and all 12 were receiving mechanical ventilation at the time of the seizures. Accompanying the increase in cerebral flow velocity was a marked increase in intracranial pressure. The cerebral hemodynamic changes appeared to reflect directly changes in systemic hemodynamic events, that is, a marked increase in blood pressure at the time of seizures. The increase in cerebral blood flow velocity with seizures, an apparent adaptive physiologic response in older individuals, may be maladaptive in the newborn infant with certain vulnerable capillary beds, such as the germinal matrix in the premature infant or the margins of an infarct in the asphyxiated infant.

Periventricular-intraventricular hemorrhage is the most important adverse neurologic event of the newborn period. It is very common and can be very severe. Such hemorrhage begins in the germinal matrix but may spread into and throughout the ventricular system. It may be accompanied by hemorrhage within the brin parenchyma. The pathogenesis of periventricular-intraventricular hemorrhage is still imperfectly understood, but relates to the anatomy and physiology of the developing cerebral vasculature and to the biophysical and biochemical environment in which that development proceeds. Periventricular-intraventricular hemorrhage may be marked by a catastrophic clinical deterioration, but is more commonly accompanied by a saltatory progression that may be difficult to detect clinically. Both concomitant neonatal disease and therapeutic intervention for such disease have been implicated in the initiation and exacerbation of periventricular-intraventricular hemorrhage. Real-time ultrasound scanning with portable instruments is now the best procedure for identifying this lesion and for assessing its sequelae. Prognosis relates principally to the severity of the lesion. Early management must be particularly directed to the maintenance of cerebral perfusion. Later management is predominantly the therapy of posthemorrhagic hydrocephalus. There is no currently available therapeutic modality that will prevent progressive posthemorrhagic hydrocephalus.

Diagnosis, prognosis, and prevention of intraventricular hemorrhage are reviewed. Diagnosis is accomplished best by real-time cranial ultrasonography. Prognosis depends primarily on the severity of any periventricular parenchymal injury that accompanies the intraventricular hemorrhage. Prevention of the hemorrhage is based on both prenatal and postnatal interventions. These can be formulated best when considered in the context of the pathogenesis, as outlined in the previous article.

The identification of intracerebellar hemorrhage in a living premature infant by real-time ultrasound scan and confirmation of the findings at autopsy are described. This represents the first demonstration of the value of this noninvasive, convenient, and safe means of brain imaging in diagnosis of this lesion. Previous studies have described the role of the computed tomography (CT) scan in identification of intracerebellar hemorrhage in the newborn. Because infants with intracerebellar hemorrhage are usually critically ill, a means of identification of the lesion that could be utilized at the bedside rather than an approach that requires transport to a CT scanner is needed. This study indicates that portable real-time ultrasound scanning can satisfy that need.

The incidence of periventricular-intraventricular hemorrhage (PV-IVH) in a group of 460 preterm infants with birth weight less than 2,250 gm, studied by cranial ultrasonography, was 39%. Sixty-four (36%) of the infants with periventricular-intraventricular hemorrhage had, in addition, periventricular intraparenchymal echodensity (IPE) evident on ultrasound scan. Thirty-three of the 64 infants had large IPE, and 31 had small IPE. Large IPE consisted of globular echodensity, most often on the side of maximum intraventricular hemorrhage, extending from the external angle of the lateral ventricle into major portions of the white matter of the frontal and parietal lobes; small IPE, often bilateral, consisted of linear echodensity extending for a few millimeters from the external angle of the lateral ventricle into the periventricular white matter. The outcome for infants with large and small IPE differed markedly. Mortality was greatest (94%) for infants with large IPE and birth weight less than 1,000 gm. All survivors with large IPE, regardless of birth weight, had moderate to severe neurological deficits evident on follow-up. In contrast, infants with small IPE and birth weight less than 1,000 gm had a mortality of 38%. Moreover, 70% of all survivors with small IPE were free of neurological deficits on follow-up. The difference in outcome appeared to relate in largest part to the severity of the parenchymal involvement. These data have major significance for decisions concerning management of infants with periventricular-intraventricular hemorrhage and intraparenchymal involvement.