Intraventricular Hemorrhage, Periventricular Hemorrhagic Infarction, and White Matter Injury

A grading approach to categorize severity of intracranial hemorrhage in preterm infants was published in the late 1970s.⁵⁸ This system remains broadly applied, both for analyses and for family counseling. However, this grading system does not include consideration for non-hemorrhagic periventricular echogenicity or echolucency, ventricular dilation due to white matter injury and loss, or cerebellar hemorrhage, which has been associated with neurodevelopmental impairment.^11,37,45,47 Nevertheless, strong associations between major intraventricular hemorrhage and adverse neurodevelopmental outcomes among preterm infants have been described in numerous single-center, multisite, and population-based analyses. However, the details of these associations may point more to a mechanism via white matter injury rather than intraventricular hemorrhage (IVH) in and of itself.

The Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN) reported the 18- to 22-month corrected age outcomes of a cohort of extremely low birth weight (ELBW) infants born in the 1990s,⁴² and found that after adjusting for numerous confounding variables, grade 3 or 4 IVH (odds ratio [OR] 2.4, 95% CI 1.8-3.1) and cystic periventricular leukomalacia (PVL) (OR 10.5, 95% CI 7.2-15.2) were associated with moderate to severe cerebral palsy (CP). Data on PVL were collected only if cystic changes were noted. Among extremely preterm infants less than 25 weeks’ estimated gestational age (EGA) in the NRN, IVH grade 3 or 4 and cystic PVL were also independently associated with moderate to severe CP.³⁰

The EPIPAGE study2,8 followed a French regional cohort of 22 to 32 weeks’ EGA infants to 2 and 5 years of age. Cerebral palsy was determined by questionnaires sent to pediatricians. At 2 years, among children with a history of white matter abnormalities (defined as PVL, ventricular dilation, or intraparenchymal hemorrhage or cyst), 24.4% were diagnosed with CP; 57% of those with cystic PVL were diagnosed with CP. The presence of cerebral lesions on neonatal CUS was independently associated with CP at 5 years. At 5 years, among those with cystic PVL, 61% had CP; among those with intraparenchymal hemorrhage, 50% had CP. At both 2 and 5 years, among those with no CUS abnormalities, CP was diagnosed in just over 4%.

In a large single-center cohort study, Hack et al. described the outcomes of ELBW infants at 20 months of age corrected for prematurity.²⁸ Severe CUS abnormality, defined as grade 3 or 4 IVH, PVL, or persistent ventricular dilatation on any CUS during hospitalization, was strongly associated with neurologic and motor abnormality (OR 8.1, 95% CI 3.7-17.7) but not with poor cognitive outcome.

The EPICure 1 study was a population-based study of infants 20 to 25 weeks’ EGA born in the United Kingdom and Ireland from March 1995 to January 1996, with follow-up at 30 months⁸⁵ and continuing through later childhood. Severe CUS abnormalities (defined as parenchymal hemorrhage, cystic changes, or ventricular dilatation on the last CUS) were associated with CP (OR 4.95, 95% CI 2.25-10.85) and with severe motor disability (OR 7.15, 95% CI 2.73-18.74). Again, when children with motor disability were excluded, severe CUS abnormality was not significantly correlated with Bayley Scales of Infant Development (BSID) mental developmental index (MDI) score.

The Extremely Low Gestational Age Newborn (ELGAN) study was a multicenter study designed to identify characteristics and exposures that increase the risk of neurodevelopmental impairments at early childhood follow-up among children born before 28 weeks’ gestation.41,55,56 Three sets of protocol scans were required at specified age ranges during NICU hospitalization. At 2 years of age, intraparenchymal hemorrhage was independently associated with CP with Gross Motor Function Classification System (GMFCS) level 2 or greater (RR 4.2, 95% CI 2.1-8.1), but white matter injury as defined by echolucency (RR 16, 95% CI 7.6-32) and ventriculomegaly (RR 11, 95% CI 5.5-21) demonstrated an even stronger association.⁴¹ However, in multivariable analyses adjusting for numerous confounders, isolated IVH without white matter lesion (as defined by parenchymal hypoechoic or hyperechoic lesion or ventriculomegaly on late CUS) did not appear to be associated with neurologic or developmental impairment at 2 years as defined by BSID II psychomotor developmental index (PDI) and MDI scores.^55,56 Only when accompanied by white matter lesions was IVH independently associated with significantly increased risk for CP, and no more than a minimal increased risk for adverse developmental outcome.

Details pertaining to extent and severity of IVH and periventricular hemorrhagic infarction may also be important to understanding implications for outcome. Severe IVH (grades III and IV) is often combined into a single “adverse” category. However, subtleties of immediate findings and trajectory of evolving injury may be important to better predict neurodevelopmental consequences. Bassan and colleagues scored the severity of periventricular hemorrhagic infarction (PVHI) on the basis of extent of the injury, bilaterality, and midline shift as seen on CUS.⁷ Overall, two thirds of those with PVHI had significant neurodevelopmental impairments, and the severity of outcome appeared to be correlated with CUS PVHI severity score. Conversely, “low-grade” (grades I and II) hemorrhage is often considered to confer no additional risk for adverse neuromotor or developmental outcomes. Yet, cortical gray matter volume reduction by volumetric MRI at near-term has been demonstrated after apparently uncomplicated IVH compared with no IVH.⁷⁹ This intriguing finding may serve to underscore that accompanying or evolving white matter injury is rarely determined or factored into predictions. Extremely low birth weight infants with uncomplicated grade I or II IVH were reported to have poorer neurodevelopmental outcomes at 20 months than those with normal CUS, even after adjusting for confounding risk factors.⁵⁹ Taylor et al.⁷⁵ described a stepwise decrement in scores on neuropsychological testing and academic achievement testing for infants with no CUS abnormalities, grade I or II, and grade III or IV, respectively. However, a recent multicenter study of extremely preterm infants (<27 weeks’ EGA) born in the recent era (2006-2008) found that 18- to 22-month outcomes did not differ for those with grades I and II than for those without hemorrhage.⁶⁰ Of note, in the National Brain Hemorrhage Study (NBHS) cohort, isolated germinal matrix and IVH without ventricular enlargement was not associated with adverse outcomes at 6 and 9 years.⁶² These disparate findings with regard to low-grade hemorrhage may be reflective of differences in patient population, era, brain imaging and outcomes ascertainment tools, and/or details of brain injury.

Normal Cranial Ultrasound and Outcomes

The risk for neurodevelopmental impairment for preterm and ELBW infants is not eliminated with the finding of a normal CUS. Nevertheless, severe CUS abnormalities are certainly more closely associated with subsequent neuromotor impairment than with developmental and cognitive outcomes, or composite neurodevelopmental outcomes. In the EPIPAGE study,2,8 only 4.4% of those with normal CUS went on to be diagnosed with CP at 2 years. In a single-center cohort of infants less than 33 weeks’ EGA from the United Kingdom, only 2% of those with normal CUS were diagnosed with disabling motor impairment at 8 years of age.⁸⁰ But of the 164 children diagnosed with CP in EPIPAGE,^2,8 more than one third had no abnormality on neonatal CUS. Hack et al.²⁸ found that abnormal CUS findings among ELBW infants were independently associated with abnormal neurologic outcome, but not with BSID II MDI less than 70, at 20 months. However, about 40% of ELBW infants with neurologic abnormality at 20 months did not have abnormal CUS, and about half of those with abnormal CUS did not go on to have neurologic abnormality. Similarly, among ELBW infants in the NICHD NRN with at least two neonatal CUS during hospitalization and all CUS reported as normal, either MDI less than 70 or CP was still present in 29% at 18 to 22 months.⁴² Further analyses demonstrate that the presence of severe IVH on CUS accounts for a very small fraction of the variation in major handicap or low MDI score¹ and that models that include clinical variables predict neurodevelopmental outcomes significantly better than do those with CUS variable alone.¹²

Potential Limitations to Interpretation: Reliability, Accuracy, and Imaging Protocols

Interpretation of the applicability of studies relating severe or low-grade CUS findings with neurodevelopmental outcomes may be challenged by the validity of findings. The NICHD Neonatal Research Network assessed interobserver reliability of CUS findings between two central readers, and accuracy of local compared with central readers.³¹ Agreement between central readers was high for major CUS findings such as grade III or IV IVH and degree of ventriculomegaly (kappa = 0.84 and 0.75, respectively), but much worse for lower grade IVH (kappa = 0.4). The sensitivity of local reader interpretation was also excellent for severe IVH (88% to 92%), but poor for grade I or II IVH (48% to 68%).

Of importance, in most of the studies discussed in the preceding except for ELGAN,41,55,56 no specific CUS protocols were required, and the frequency of CUS was not specified. The typical timing and frequency of CUS screening for preterm infants may be inadequate to appropriately delineate subtle or transient findings. A primary guideline for CUS screening in the United States is the Practice Parameter for Neuroimaging of the Neonate in 2002,⁵¹ which recommends screening with CUS for all infants with EGA less than 30 weeks at 7 to 14 days, and “optimally” again at 36 to 40 weeks. However, more frequent and detailed surveillance protocols using high-resolution techniques may substantially increase the sensitivity of CUS for identifying infants at high risk for adverse outcomes.^19,20,43 de Vries et al.²⁰ performed CUS at least weekly on all infants less than 36 weeks’ EGA from admission until discharge or to 40 weeks’ postmenstrual age (PMA), and images scored not only according to grade of hemorrhage, but also duration of periventricular echodensity, presence of cystic findings, basal ganglia echogenicities, and evidence of focal infarction. With this approach, the sensitivity and specificity of major CUS abnormalities for CP at 2 years was an impressive 76% and 95% for patients less than 32 weeks’ EGA, and 86% and 99% for those 33 to 36 weeks. Among those with major CUS abnormalities who developed CP, 30% had major CUS abnormalities that were first detected after 28 days, including some cystic changes that were found only on late scans or were observed to collapse or coalesce over time.⁶¹ With the approach to CUS scanning used by deVries et al., the negative predictive value of major CUS abnormalities for CP was 99% and the positive predictive value was 48% for less than 32-week EGA infants. Major CUS abnormalities were not strongly associated with cognitive delay at 2 years.

It is clear that with optimal protocols performed by highly skilled hands, CUS alone can be a valuable tool to assist in prediction of neuromotor outcomes. However, CUS and outcomes studies have implicated white matter injury as the important underlying etiology linking abnormal CUS findings with adverse neurodevelopmental outcomes among preterm infants. This leads to the suggestion that if we can better recognize and more comprehensively characterize white matter injury, we may better be able to predict adverse motor and developmental outcomes, and potentially anticipate specific needs for early evaluation and intervention. Perhaps as important, if we can better understand the connection between perinatal events and brain injury, we may be able to prevent or ameliorate brain injury in the preterm altogether. These broad hypotheses have formed the basis for investigation of magnetic resonance imaging as a routine or adjuvant neuroimaging modality for preterm infants.

White Matter Injury

A major focus of interest and study for preterm neuroimaging and outcomes has been on white matter injury. As described, CUS markers of white matter injury have been shown to be risk factors for adverse neuromotor outcomes. White matter injury, such as cystic PVL and ventriculomegaly caused by periventricular white matter loss, should be easily detectable by CUS. On the other hand, CUS does not detect diffuse white matter injury or subtle white matter lesions as well as MRI (Figure 69-1).^14,49 A relatively low sensitivity of CUS for detection of noncystic white matter abnormalities has been found in multiple studies,^21,34,52 although many of these studies have not performed frequent sequential scans during the neonatal period. Existing and increasing evidence points to the fact that white matter injury in preterm infants is associated with broader brain maturational disturbances. White matter injury on MRI in preterm infants is associated with reduced cortical and deep gray matter volume^10,35 and with decreased hippocampal volumes, which in turn is associated with lower developmental scores and working memory in early childhood.^46,74 Pre-oligodendroglial cells of the developing white matter are known to be vulnerable to a number of perinatal and neonatal clinical factors, including hypoperfusion, systemic inflammation, and infection.^81,84 But perhaps more important than direct injury to developing white matter, subplate neurons, and axonal growth and elongation processes is the resulting reduced connectivity affecting the cerebral white matter, deep gray matter, cortex, and cerebellum.^29,38,50 Reduction of crucial connections during a period in rapid brain development can impair neuronal differentiation and, subsequently, gray matter growth.⁸² Several classification systems have been used to “score” or “grade” white matter injury by MRI.^34,52 A scoring system for term equivalent age MRI abnormalities has included cerebellar injury and volumetric measures.⁴⁰

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