Relevant Neuropathology.

The hallmark of the encephalopathy of prematurity is cerebral white matter injury or PVL (see Chapter 14 ). To understand the value and the challenges of neuroimaging of the encephalopathy in the neonatal period, we should review briefly the neuropathology of PVL and related cerebral white matter injury. PVL consists of two distinct components: focal necrosis , with loss of all cellular elements, dorsal and lateral to the lateral ventricles, and a more cell-specific diffuse injury involving pre-oligodendrocytes (pre-OLs) in cerebral white matter and marked by astrogliosis and microgliosis. A spectrum of severity is recognized and in living infants is based on neuroimaging (principally MRI). Thus PVL can be categorized into three subtypes ( Table 16.5 ). The most severe form involves focal necroses that are macroscopic in size, that is, relatively large, more than several millimeters, and evolve to tissue dissolution and cystic change over a period of weeks. This focal necrotic/cystic form is often simply termed cystic PVL ( Fig. 16.1 ) and is readily detected by cranial ultrasonography or MRI (see later). Cystic PVL is now uncommon and has an overall incidence in living VLBW infants of 5% or less. In the largest neuropathological series of preterm infants ( n = 41), approximately 40% exhibited PVL with focal necroses, but macroscopic necroses were observed in only 18% of these PVL cases (only 7% of the total of autopsied preterm infants). A moderate form of PVL involves focal necrotic lesions that are 1 to 2 mm in size and, on tissue dissolution, evolve not to cysts but rather to focal glial scars, sometimes visible as punctate areas of increased signal intensity on T ₁ -weighted MRI ( Fig. 16.2 ). This form, often termed noncystic PVL , occurs in approximately 25% of living infants. Finally, the least severe form of PVL involves a focal necrotic component less than 1 mm in size, that is, microscopic and so small as to be invisible to neuroimaging. This mild form, like all forms of PVL, exhibits the diffuse gliosis described in Chapter 14 . The degree of the diffuse abnormality generally correlates with the severity of PVL (see Table 16.5 ). The MRI correlate of the diffuse gliosis likely is the diffuse signal change described later. The mild form of PVL is likely present in a substantial minority of premature infants (see later). In the neuropathological series just noted, fully 82% of PVL cases (34% of the total series of autopsied premature infants) had focal necrotic lesions that were less than 1 mm and therefore likely below the detection of conventional clinical MRI scanners. Such cases would be classified (mistakenly) as nonnecrotic by MRI. All three subtypes of PVL include the diffuse component, characterized by astrogliosis/microgliosis, and, after the initial pre-OL cell death, an excess of oligodendroglial progenitors. These oligodendroglial progenitors, however, fail to differentiate into myelin-producing cells (see Chapters 14 and 15 ). The severity of the diffuse component appears to parallel the severity of the PVL.

Images of severe cystic periventricular leukomalacia.

(A) A parasaggital ultrasound image showing numerous large cysts superolateral to the lateral ventricle (arrow) . (B) A coronal T ₂ -weighted image in which cysts are present superolateral to the lateral ventricles (arrow) .

Axial T ₁ -weighted images showing examples of noncystic PVL visible as areas of increased signal intensity in the periventricular areas (arrows) . The severity of injury increases from panels A to B to C.

A form of cerebral white matter injury with no necroses and only the diffuse white matter gliosis must be considered . It is noteworthy that in the total group of 41 autopsied premature infants by Pierson et al., approximately 40% had only diffuse gliosis, with no focal necroses. In strict terminology, these cases without any necroses should not be termed PVL . This diffuse-lesion-only may be the least severe form of cerebral white matter injury, but because its MRI appearance is likely identical to the least severe form of PVL, that is, with microscopic necroses, distinction in vivo is not currently possible . Whether these infants consistently exhibit diffuse signal abnormality on MRI is unknown. Moreover, whether infants with the diffuse gliotic component without any necrotic component subsequently exhibit the neuronal/axonal dysmaturational effects of the encephalopathy of prematurity also is not known. The particular potential importance of diffuse white matter gliosis without focal necroses relates not only to its high frequency in neuropathological studies of premature infants, but also to the recent observations of Buser et al., who not only confirmed the high frequency but who also showed in cerebral white matter the characteristic excess of pre-OLs and their maturational arrest , as observed in the diffuse component of PVL. These findings suggest that such infants in vivo could develop the impairment of myelination and perhaps also the secondary dysmaturational effects on neuronal/axonal structures consequent to disrupted myelination (see Chapter 14 ). The important point in this context is that accurate identification of the diffuse white matter cellular abnormalities in vivo in the neonatal period currently is not clearly possible . Experimental data based on imaging at 11.7T suggest potential for identifying and quantifying white matter gliosis (as well as microscopic necrosis). However, the imaging was carried out ex vivo , and the safety of imaging human preterm brain at 11.7T has not been established.

Cranial Ultrasonography.

Cranial ultrasonography is of great value in diagnosis ( Tables 16.6–16.8 ). The cysts of cystic PVL are readily visible by cranial ultrasonography (see Table 16.6 ; Figs. 16.3–16.5 ). They are located primarily just lateral to the atria of the lateral ventricles, and extend anteriorly, and to some extent posteriorly, with increasing severity ( Fig. 16.6 ). They are sometimes only visible for a few weeks and may have fully resolved by term equivalent, but their presence is predictive of subsequent cerebral palsy. Their resolution is likely due to development of a gliotic scar with collapse of the cyst (see Chapter 14 ; Fig. 16.7 ). As a result, their manifestation at term equivalent may be subtle, consisting of mild to moderate ventricular dilatation and an irregularly contoured ventricular wall.

Coronal ultrasound scans of periventricular leukomalacia in a premature infant on postnatal days (A) 5 and (B) 24. Note in A, the periventricular echodensities (arrows) and in B, the small echolucent foci, consistent with cysts, in the same areas (arrows) .

Coronal ultrasound scans angled slightly posteriorly to image the peritrigonal regions in periventricular leukomalacia. The scans were obtained in a premature infant at (A) 10, (B) 17, and (C) 25 days of age. Note the evolution from echodensities to multiple small echolucencies in the periventricular white matter.

Parasagittal ultrasound scans of periventricular leukomalacia obtained from a premature infant at (A) 2, (B) 13, (C) 17, and (D) 26 days of age. Note the evolution from echodensity to multiple small echolucencies in the periventricular white matter adjacent to the trigone of the lateral ventricles.

Odds ratio maps of noncystic periventricular leukomalacia (PVL) for motor (second column) , cognitive (third column) , and language (fourth column) outcomes overlaid on a T ₁ -weighted neonatal brain template. The first column shows the spatial cumulative map including all noncystic signal abnormalities seen in any of 58 very preterm neonates. Note that the signal intensity abnormalities most commonly involve the white matter adjacent to the trigone and posterior body of the lateral ventricles. Note also that they also tend to involve the left hemisphere more than the right. The maximum odds ratio values on the motor, cognitive, and language odds ratio maps are 63.8, 78.9, and 17.5, respectively.

(From Guo T, Duerden EG, Adams E, et al. Quantitative assessment of white matter injury in preterm neonates: association with outcomes. Neurology . 2017;88:614–622.)

Parasagittal ultrasound scans obtained from a premature infant at (A) 24 and (B) 93 days of age. Note that the echolucent cysts apparent at 24 days have disappeared by 93 days of age. The trigonal region of the lateral ventricle at 93 days is dilated because of loss of periventricular white matter and failure of early myelination.

The ultrasonographic imaging correlates of noncystic PVL are generally not obvious (see Tables 16.7 and 16.8 ). Some data suggest that cerebral white matter echodensity at least as echogenic as the choroid plexus and persisting for at least 7 days is significant. Further, the presence of white matter inhomogeneity or a patchy appearance on ultrasonography should also alert the clinician to potential white matter abnormalities ( Fig. 16.8 ). This patchy appearance can sometimes be hemorrhagic in origin, and a combination of diffusion- and susceptibility-weighted MRI can help identify a hemorrhagic component. Although PVL is principally a nonhemorrhagic lesion, occasionally secondary hemorrhage can be dramatic ( Fig. 16.9 ).

Coronal ultrasound scan in a 28-week preterm infant on day of life 5 shows periventricular white matter echodensity (A). Note the corresponding lesion that appears dark on the T ₂ -weighted image ( arrowhead, B) obtained at term equivalent age.

Ultrasound scan of hemorrhagic periventricular leukomalacia from an infant of 33 weeks of gestation who experienced cardiorespiratory arrest at 20 days of age. (A) Coronal section shows ovoid echodense area in right periventricular region (long arrow) ; a smaller periventricular echodense area is present on the left. The lateral ventricles are marked by short arrows. (B) Right parasagittal scan shows extensive anteroposterior region of periventricular echodensity (arrowheads) . (C) Coronal section of cerebrum from the same infant, who died several days later, shows massive hemorrhagic periventricular leukomalacia on the right and a smaller area on the left.

Magnetic Resonance Imaging.

The focal necrotic/cystic component of PVL, observed well on cranial ultrasound, is readily demonstrated by MRI as well (see Table 16.5 ). However, the much more common moderate (noncystic) forms of PVL often also are detected by MRI and generally not by cranial ultrasonography (see Table 16.7 ). Indeed, the high frequencies of noncystic cerebral white matter abnormality, manifested either as focal punctate white matter lesions or, even more commonly, of the mildest form of PVL (with microscopic necroses), manifested only as diffuse MRI signal change, were unexpected until the application of MRI (see Table 16.5 ). The frequency of the diffuse abnormality on MRI increases as a function of postnatal age . In one series with serial MRI scans, the finding of diffuse MRI signal abnormality in premature infants with a median gestational age of 27 weeks increased from 21% in the first postnatal week, to 53% over the next several weeks, to 79% at term equivalent. In a later prospective study of 100 premature infants, 64 exhibited white matter signal abnormality at term.

The neuropathological correlates of the diffuse white matter signal abnormality, known as diffuse excessive high signal intensity (DEHSI), are unclear. A reasonable speculation is that the abnormality reflects the diffuse gliotic (astrogliosis and microgliosis) component of PVL. It is seen best on T ₂ -weighted images at term equivalent age and is a common finding (see earlier). While these white matter signal intensity changes are associated with increased water diffusion coefficient values on diffusion imaging, the qualitative identification of signal changes on T ₂ -weighted images is subjective. Further, recent studies have failed to identify a relationship between these signal changes and outcome at either 18 or 30 months of age. However, the absence of a later clinical correlate to DEHSI does not necessarily mean that a degree of white matter injury isn’t present. Indeed, in the neuropathological series referred to earlier, the focal necrotic component was less than 1 mm in most cases and likely below the resolution of clinical MRI scanners. Moreover, as noted earlier, in 42% of the entire series of autopsied premature infants diffuse gliosis without focal necrosis was present. Whether the subsequent neuronal/axonal abnormalities observed in the encephalopathy of prematurity and likely important for long-term outcome were present is unknown. Moreover, the lack of later clinical abnormalities also could reflect the beneficial effects of plasticity.

Other potential MRI correlates of diffuse cerebral white matter injury in the neonatal period include disturbances of white matter structure detected via diffusion anisotropy maps ( Fig. 16.10 ) and abnormalities of ¹ H spectroscopy, with both involving areas of white matter that may appear normal on conventional, T ₁ – and T ₂ -weighted, imaging.

Diffusion vector maps overlaid on coronal diffusion weighted images for a premature infant at term with no white matter injury (A) and a premature infant at term with perinatal white matter injury (B). The posterior limb of the internal capsule (I.C.) in (A) shows more homologous directed vectors that are longer and more densely packed than in the internal capsule of (B). Anteroposterior-oriented white matter fibers in the area of the superior longitudinal fasciculus ( S.L.F. ; yellow and green dots with yellow representing higher anisotropy than green) in (A) indicate the presence of fiber bundles that are missing or are less prominent in (B). The only discrete anteroposterior fiber bundles that definitely are present in (B) are the cingulate bundle (C.B.) . Fibers of the corona radiata appear less well-organized in (B) than (A).

(From Huppi PS, Murphy B, Maier SE, et al. Microstructural brain development after perinatal cerebral white matter injury assessed by diffusion tensor magnetic resonance imaging. Pediatrics . 2001;107:455–460.)

Spastic Diplegia.

Premature infants may exhibit a variety of major motor deficits related to PVL, severe IVH (see Chapter 24 ), and stroke (see Chapter 21 ), among other pathologies. In the context of this chapter on the encephalopathy of prematurity, the principal major motor deficit is spastic diplegia . This motor disturbance has as its central feature spastic paresis of the extremities with affection of lower more than upper limbs. The incidence of this motor deficit has declined markedly in the past two decades and is generally approximately 2% to 3%, although in the extremely preterm infant the incidence can be as high as 10%.

Two major lines of evidence indicate that the focal necroses of PVL result in spastic diplegia and its variants. First, the topography of the focal lesions includes the region of cerebral white matter traversed by descending fibers from motor cortex, and those subserving function of lower extremities are more likely to be affected by the periventricular locus of the necrosis ( Fig. 16.11 ). More severe lesions, with lateral extension into the centrum semiovale and corona radiata, would be expected to affect upper extremities and intellectual functions as well. Indeed, patients with spastic diplegia with significant involvement of upper extremities exhibit other manifestations of more severe cerebral disturbance, including intellectual deficits ( Table 16.10 ).

Schematic diagram of corticospinal tracts from their origin in the motor cortex, with descent past the periventricular region and into the internal capsule. The locus of periventricular leukomalacia (marked square areas) would be expected to affect, particularly, descending fibers for lower extremity more than the laterally placed fibers for upper extremity and face.

A second line of evidence linking spastic diplegia and focal PVL, related to the first, is that the ultrasonographic and MRI correlates of the focal necrotic component of PVL, especially cystic PVL, are associated with spastic diplegia. The severity and extent of injury, as manifested by cystic change or ventricular dilation or both, are correlated with more severe involvement of lower limbs, prominent involvement of upper limbs, and impairment of cognitive function. Further, in a study in which the location of cysts and/or signal abnormality on MR was compared with motor outcome, cysts located more anteriorly, near the corticospinal tracts, were most strongly associated with motor deficits (see Fig. 16.6 ). The motor deficits in premature infants with mild spastic diplegia may disappear in the first several years of life, especially if the white matter lesions are noncystic by ultrasonography.

In addition to the evidence cited above indicating that spastic diplegia is caused by periventricular injury to descending corticospinal tracts, injury to thalamocortical sensory afferents may also play a role in the motor deficits associated with PVL. Several studies using diffusion tensor imaging with diffusion anisotropy measures (see Chapter 10 ) to evaluate white matter integrity found correlations between the degree of white matter abnormality in thalamocortical tracts and motor deficits in older children who had been born prematurely. Thus it has been hypothesized that disruption of sensorimotor loops involved in motor control plays an important role in the motor deficits associated with PVL. Nevertheless, in a recent report in which both corticospinal and thalamocortical tracts were assessed, correlation of motor dysfunction in spastic diplegia was greater for impairment of the former than the latter.

Other Motor Disturbances.

At least one-half of preterm infants exhibit motor disturbances despite the absence of cerebral palsy ( Table 16.11 ). These include difficulties in gross and/or fine motor skills, involving especially balance, visual motor integration, hand-eye coordination, manual dexterity, and related motor impairments. These disturbances are manifest in infancy as delayed motor milestones; at school age with impairment in activities ranging from running, ball skills, and drawing; and in adolescence and adulthood with clumsiness and dyscoordination. Although these deficits are minor in comparison to cerebral palsy, they are much more common and may affect quality of life.

The clinicopathological correlates of these disturbances are likely multiple. In keeping with a relation to the white matter injury of the encephalopathy of prematurity, long-term follow-up studies of preterm infants with white matter signal abnormalities detected on conventional (T ₁ – and T ₂ -weighted) MRI at term equivalent were strongly predictive of motor impairment at ages 2 and 5 years. Further, diffusion abnormalities of white matter, including the internal capsule and corticospinal tracts, have been associated with similarly abnormal motor outcomes. Whether gray matter structures involved in the encephalopathy of prematurity, for example, basal ganglia and thalamus, are involved seems likely, but has not been studied specifically. Recent work suggests importance also for cerebellar impairment. More data are needed on this important issue.

Cognitive Deficits.

Cognitive performance involves a complex series of functions that can be parsed in many ways. In this section, we review overall intelligence quotient (IQ) measures (often from younger populations) followed by outcome measures involving more specific cognitive functions, including language and executive function (EF) ( Table 16.13 ).

Concerning overall cognitive performance , fully 30% to 50% of very preterm survivors exhibit cognitive deficits, and as a group, preterm infants have lower developmental quotients than their term-born counterparts. In a meta-analysis published in 2002, the weighted mean difference in cognitive scores of preterm and term-born control infants was 10.9 (95% CI 9.2 to 12.5). This difference was directly proportional to gestational age or weight at birth, with values ranging as high as 22.7 (95% CI 16.3 to 29.1) for infants born weighing less than 750 g. A 10-point reduction in IQ has significant meaning for an individual child, but also has meaning at a group level. For example, if one assumes, as an approximation, that the standard deviation of IQ values is similar between term and preterm children, a 10-point reduction in the mean value (from 100 to 90) corresponds to an increase in the fraction of children with IQ below 85 from 16% to 37%, and an increase in the fraction with IQ below 70 from 2.5% to 9%. This shift in distribution has social consequences, and it is well known that preterm children require a disproportionate amount of follow-up resources.

Concerning the clinicopathological correlates of the cognitive deficits in premature infants, consistent with the concept of the encephalopathy of prematurity, white matter injury appears central. A relation of severe cognitive deficits to white matter involvement is apparent in infants with cystic PVL and spastic involvement of both upper and lower extremities, as described earlier (see Table 16.10 ). Notably, most infants with noncystic PVL exhibit only minor motor deficits, but prominent cognitive disturbance. Involvement of cerebral white matter fibers subserving visual, auditory, somesthetic, and associative functions may be crucial in this context. Indeed, the peritrigonal region, a site of predilection of PVL, is a region containing a high concentration of interhemispheric callosal commissural fibers, intrahemispheric associative fibers, and ascending (thalamocortical) and descending (cortical to deep nuclear structures and to brain stem/cord) projection fibers. In an assessment of the relationship between the amount of white matter involved with PVL and cognitive outcome, the involvement of frontal white matter particularly predicted adverse cognitive and motor outcomes (see Fig. 16.6 ). However, this regional distinction is not dramatic and has not been emphasized by others.

The importance of white matter injury in relation to cognitive outcome was suggested by a series of studies that reported an association of impaired neurodevelopment in premature infants studied in later infancy, childhood, and adolescence in whom neuroimaging during the neonatal period showed white matter signal abnormality, ventricular dilation, and qualitative measures of diminished white matter volume. The largest well-characterized study to date ( n = 167) of VPT (<30 weeks’ gestation) showed clearly the relationship between the frequency and severity of these neonatal MRI measures (obtained at term equivalent age) and subsequent cognitive motor deficits (see Table 16.13 ). The increasing severity of white matter injury was accompanied by such abnormalities of gray matter as increased size of the subarachnoid space and impaired gyral maturation. The likely relation of the latter dysmaturation to primary injury to white matter was detailed in Chapters 7 and 14 . Since the seminal work just described, there have been a large number of studies principally confirming the earlier observation. White matter abnormality can also be quantified with diffusion imaging, particularly through measures of diffusion anisotropy (see Chapter 10 ). For example, in a study of preterm children with follow up at 2 years, cognitive scores were correlated with anisotropy values in the corpus callosum.

Consistent with the concept that primary cerebral white matter injury is related to the secondary developmental disturbances of cerebral cortex, thalamus, and basal ganglia seen in premature infants (see Chapter 14 ), a particularly detailed MRI study defined a common neonatal image phenotype that appeared to predict adverse neurodevelopmental outcome in children born preterm. Based on a study of 80 preterm infants (mean gestational age 29 weeks) by MRI at term equivalent age, Boardman and collaborators delineated the common image phenotype as diffuse white matter injury and tissue volume reduction in the thalamus, globus pallidus, periventricular white matter, corona radiata, and central region of the centrum semiovale. The abnormal image phenotype was associated with reduced median DQ (DQ = 92) at 2 years compared with control infants (DQ = 112). In a similar study of adolescent children, Soria-Pastor et al. also found that lower white matter volume was associated with IQ and processing speed.

Because our current concept of the encephalopathy of prematurity involves primary white matter injury leading to secondary dysmaturation of gray matter structures (see Chapter 14 ), it would be predicted that imaging studies of preterm infants later in life would show evidence of such developmental disturbances. Gray matter tissue signal abnormalities in preterm infants are less common in the neonatal period than are white matter signal abnormalities, perhaps consistent with the uncommon occurrence of acute neuronal injury. Gray matter abnormality is more typically manifest near term equivalent age as alterations of cortical folding and/or enlarged extracerebral spaces . As discussed in Chapter 7 , dramatic changes in cortical folding take place during the third trimester of gestation. This process can be disrupted in preterm infants. For reasons that have not been fully elucidated, these cortical folding abnormalities most commonly involve the temporal and inferior frontal areas as well as the cingulate sulcus. In a study of 167 VPT, gray matter abnormalities were found in half of the infants and consisted of abnormal/immature cortical folding patterns and/or enlarged subarachnoid space. These abnormalities were associated with an increased risk of severe cognitive delay, psychomotor delay, and cerebral palsy at age 2 years, but the association was less robust than that with white matter abnormalities in the same study. The potential links between cerebral white matter injury and cortical folding abnormalities were discussed in Chapter 7 , but may involve impairment of late migrating GABAergic neurons to superficial layers of cerebral cortex or of tension generated by underlying developing white matter. Perhaps more promising markers of cerebral cortical maturational impairment and subsequent outcome will include the cortical folding measures outlined recently by Shimony et al. (see Chapter 7 ). In a study of neurodevelopmental outcomes in preterm children in which correlations were sought between abnormalities on MRI at term equivalent age and outcome at age 7 years, T ₁ – and T ₂ -weighted MRI studies were scored for signal abnormality and/or volume loss in white matter, cortex, deep nuclear gray matter, and cerebellum. Higher global, deep gray matter and cerebellar as well as white matter abnormality scores were related to poorer IQ and motor function ( Fig. 16.12 ). Notably, abnormalities of the area of basal ganglia showed a strong relation to cognitive outcome. While area reduction could be related to direct injury to deep nuclear gray matter, it is more likely that basal ganglia area reduction reflects a disruption of reciprocal connections between basal ganglia and cortex as a consequence of white matter injury or cortical dysmaturation or both (see Chapter 14 ).

A plot showing the relationship of magnetic resonance imaging findings at term equivalent age for 186 preterm children and neurodevelopmental outcome at age 7 years. Full scale IQ was measured using the Wechsler Abbreviated Scale of Intelligence. Word, reading, spelling, and math computational skills were assessed with the Wide Range Achievement Test —Fourth edition. Motor skills were assessed using the Movement Assessment Battery for Children. Parents rated their child’s behavior using the Strengths and Difficulties Questionnaire (SDQ) (note that for this test, higher scores indicate worse outcome). CGM, Cortical gray matter; DNGM, deep nuclear gray matter; WMA, white matter abnormality.

(From Anderson PJ, Treyvaud K, Neil JJ, et al. Associations of newborn brain magnetic resonance imaging with long-term neurodevelopmental impairments in very preterm children. J Pediatr. 2017;187:58-65 e51.)

In addition to findings on conventional MRI, MR volumetry (see Chapter 10 ) has also been applied to evaluate preterm children and outcomes. Widespread alterations in cerebral volumes have been described for preterm infants imaged at term equivalent age, and a number of studies have related volume changes with neurodevelopmental outcome. At short-term follow-up (<2 years), neurodevelopmental disability was associated with volumetric reductions in cerebral white matter, cerebral cortex, deep nuclear gray matter, hippocampus, total cerebral tissue, and cerebellum.

EF is a broad term that refers to coordination of many interrelated processes and involves purposeful, goal-directed behavior that is instrumental in cognitive, behavioral, emotional, and social functions. While there is not yet consensus on the exact components of EF, it may be considered to include cognitive flexibility, goal setting, attentional control, and information processing. Executive dysfunction, then, is not a unitary disorder, but reflects a range of impairment phenotypes.

One of the functional implications of executive dysfunction is poor academic performance (which may also be caused by low IQ), and a number of studies have shown poorer academic performance for preterm children on standardized testing. Deficits in academic performance may also be manifest as learning disability. In a study of 75 children weighing less than 800 g at birth who had a verbal or performance IQ ≥85, 65% of preterm children met criteria for learning disability, as compared with 13% of the control group. Findings on subtests were consistent with the large body of evidence showing that academic underachievement arises, at least in part, from executive dysfunction.

Concerning clinicopathological correlations, the association between imaging findings and executive/academic dysfunction in preterm children has been evaluated in multiple studies. In the study noted earlier with outcomes at age 7 years (see Fig. 16.12 ), higher cerebral white matter, deep gray matter, and global abnormality scores were related to spelling and math computation. Studies focused on white matter injury have also noted associated impairments in executive functioning, verbal and visuospatial working memory, and learning. Overall the frequent concurrence of cerebral white matter abnormality with disturbances of gray matter structures is consistent with the central concept of the encephalopathy of prematurity.

Language delay is common in preterm children (see Table 16.12 ). The language and communication problems are often attributed to delayed development with the expectation of later catch-up. However, meta-analysis indicates that language deficits persist in preterm children with a severity comparable to that documented in other cognitive domains. The language deficits affect quality of life, including friendship quality, reading skills, and overall academic achievement. Language function can be divided into simple (vocabulary words and short phrases) and complex (wording, meaning of concepts, use of verbs, relational terms, and complex sentences). In a meta-analysis, preterm children were found to lag behind term control children in both simple (0.5 SD, 95% CI 0.3 to 0.6) and complex (0.6 SD, 95% CI 0.4 to 0.8) language measures.

When considering the imaging correlates of language dysfunction, current concepts indicate that the anatomical substrate of language function involves widely distributed areas. Functional MRI studies show that language networks are detectable in preterm infants, despite the fact that the infants will not have any fluent speech for more than a year. The imaging correlates of language impairment in preterm children are likely multiple, but white matter disturbance is identified commonly. For example, white matter injury has been associated with impaired language skills. Cerebellar lesions in the absence of overt cerebral lesions have also been associated with abnormalities of receptive and expressive language. Recall, however, that most cerebral white matter injury in premature infants may be below the resolution of conventional MRI (see earlier). Further, reduced corpus callosum volumes, consistent with white matter injury, have been related to impaired verbal fluency.

Behavioral Disturbances.

Especially common sequelae in premature infants involve behavioral issues, especially attention-deficit/hyperactivity disorder ( ADHD ). ADHD is relatively common among preterm children, with prevalence rates of 10% to 20%. In a recent meta-analysis, preterm children had a relative risk of 2.64 compared with term-born children. The prevalence also varies with degree of prematurity, and in one study was 17% for infants born weighing less than 750 g as compared with 6% in infants weighing 750 to 1499 g at birth. ADHD has been associated with such neonatal medical factors as chronic lung disease, sepsis, and necrotizing enterocolitis, as well as intracranial hemorrhage and white matter injury. It has also been suggested that reduction of perinatal systemic inflammation could reduce the incidence of ADHD. Notably, systemic inflammation is an important precipitant of cerebral white matter injury (see Chapter 15 ). There are relatively few studies linking imaging abnormalities with attentional difficulties in preterm children, but one study comparing MRI at term equivalent age with outcome at age 7 years found that the strongest link with attention difficulties was abnormalities in deep nuclear gray matter. The latter are commonly associated with cerebral white matter injury in the encephalopathy of prematurity.

Socialization Deficits—Autism Spectrum Disorders.

Approximately 20% of preterm toddlers have abnormalities on early screening tests for autism spectrum disorder (ASD), such as the Modified Checklist for Autism in Toddlers (MCHAT), suggesting that they are at high risk for ASD. Major motor, cognitive, visual, and hearing impairments may lead to false- positive screening tests, and these impairments may account for more than half of the positive MCHAT screens in extremely low gestational age newborns. Nevertheless, even after those with such impairments are eliminated, 10% of children—nearly double the expected rate—screen positive. The perinatal clinical correlates of ASD and other social/behavioral issues in preterm infants are not yet fully delineated. However, the risk of ASD does increase with the degree of prematurity, either with or without intellectual disability. From a neuroimaging standpoint, ASD has been associated with cystic white matter lesions and cerebellar abnormalities during the perinatal period, although in studies with relatively small numbers of subjects.

Visual Deficits.

A number of injuries can lead to visual impairment in preterm children, ranging from retinopathy of prematurity (ROP) through injury to white matter visual pathways, thalamus, and cerebral cortex. In this section, we focus primarily on visual impairment caused by brain injury. Much of the visual impairment found in preterm children can be classified as cortical or cerebral visual impairment (CVI), which is defined as bilateral impairment of visual acuity due to damage to cerebral visual areas. In a study of 105 preterm infants and 67 control infants, 24% of the preterm children met criteria for CVI, compared to 7% of controls (OR 3.86, 95% CI: 1.40 to 10.70). Several studies have evaluated the association between brain injury and visual impairment. Perhaps not surprisingly, PVL has a strong association with visual impairment, as the primary area of injury includes the optic radiations (geniculocalcarine tracts) and visual association fibers. More severe PVL correlates with poorer future vision, and lesions of the peritrigonal white matter and optic radiations, as well as of the occipital cortex, have been associated with abnormality of visual acuity and function.

CVI, though defined on the basis of visual acuity, is also associated with impaired visual perception and visual-motor integration. Geldof et al. have proposed that these impairments are related to injury involving occipital-parietal-frontal neural circuitries. These circuitries are mediated by cerebral white matter regions particularly likely to be affected in cerebral white matter injury in premature infants. Consistent with the importance of cerebral white matter injury in recovery is the finding that only 42% of children with PVL and CVI show improvement in visual function, a proportion considerably lower than the 78% of a heterogeneous group of infants with primarily striate cortical injury.

A number of studies have evaluated the relationship between the quality of MRI diffusion parameters of the geniculocalcarine tract (usually fractional anisotropy, see Chapter 10 ) and visual function. In general, higher anisotropy values corresponded to better visual function. In one study of 142 preterm children and 32 control children who were evaluated at age 7 years, diffusion abnormalities were also found in association with white matter injury on conventional MRI and with ROP. The association of abnormalities of the geniculocalcarine tract with ROP suggests that cerebral white matter changes not only can cause visual impairment, but can be caused by other abnormalities. In the case of ROP, it has been postulated that the abnormalities of the geniculocalcarine tract are a consequence of trans-synaptic effects. Other studies concerning structure function relationships include a volumetric study in which reduced occipital regional volumes were associated with impaired visual function.

Antibiotics.

In a subset of infants, maternal intrauterine infection and fetal systemic inflammation appear important in pathogenesis of cerebral white matter injury (see Table 16.14 ; see Chapter 15 ). Moreover, maternal intrauterine infection is a major cause of spontaneous preterm labor. A study of over 4000 women in spontaneous preterm labor compared administration of erythromycin and/or amoxicillin-clavulanate with that of placebo. At age 7 years the children administered either antibiotic regimen showed no benefit in functional attainment , those administered erythromycin showed an increase in functional impairment, and those administered either antibiotic regimen showed an increase in risk of cerebral palsy . Thus the routine use of antibiotics is not of apparent benefit in mothers in spontaneous labor. In a separate study, the use of erythromycin in preterm labor with premature rupture of membranes led to a small reduction in adverse short-term neonatal outcome, but the adverse effect of erythromycin in the study just described raises questions about the merit of this practice. Note that these data do not address the antibiotic treatment of overt chorioamnionitis in mothers with premature rupture of membranes or mothers with positive Group B streptococcal cultures (see Chapter 35 ).

N -Acetylcysteine.

Another antenatal attempt to combat the effects of intrauterine infection/systemic inflammation involves the use of N -acetylcysteine (NAC; see Table 16.14 ). NAC is a free radical scavenger that, in experimental models of chorioamnionitis, has been shown to cross the blood-brain barrier, decrease oxidative stress, and exhibit multiple antiinflammatory effects. In a recent study of mothers with chorioamnionitis, 22 were randomized to receive either intravenous NAC or saline before delivery and for 2.5 days past delivery. In saline-treated infants cerebrovascular autoregulation was impaired, but in NAC-treated infants this critical parameter, a potential precursor to hypoxic-ischemic injury, was preserved. Whether this apparent beneficial effect will lead to prevention of brain injury or dysfunction will require a larger study. Nevertheless, the data are of interest.

Hypoxemia.

Avoidance of oxygen deprivation is a cornerstone of supportive therapy. Hypoxemia may lead to a disturbance of cerebrovascular autoregulation and, as a consequence, a pressure-passive circulation ( Table 16.15 ; see Chapter 13 ). Under such circumstances, the infant is vulnerable to ischemic cerebral white matter injury with only moderate decreases in arterial blood pressure (see Chapter 15 ). Indeed, this hemodynamic mechanism may be the most important by which hypoxemia leads to parenchymal injury. The propensity for white matter injury presumably relates in part to the limited vasodilatory capacity in neonatal cerebral white matter in the presence of anaerobic glycolysis, increased substrate demand and a cellular population, pre-OLs, exquisitely vulnerable to hypoxia-ischemia and resulting oxidative attack (see Chapter 15 ).

Concerning detection and causes of hypoxemia , very diligent surveillance is critical. The use of pulse oximetry and transcutaneous oxygen monitoring has demonstrated that among infants in neonatal intensive care facilities, especially low-birth-weight infants, episodes of hypoxemia are more frequent than often thought and are readily overlooked by periodic sampling of arterial blood. Thus continuous transcutaneous oxygen or pulse oximetry monitoring in sick, low-birth-weight infants has detected some very frequent and, in some cases, previously unsuspected causes of hypoxemia ( Table 16.16 ).

Continuous transcutaneous oxygenation measurement via pulse oximetry has become standard practice, but it would be more relevant to measure cerebral oxygenation via near infrared spectroscopy (NIRS; Chapter 10 ). For example, NIRS has been used to show that hypoxemia with apnea results in cerebral deoxygenation. In a multicenter, phase II, randomized trial of 166 infants born at less than 28 weeks’ gestation, continuous NIRS monitoring was used during the first 72 hours of life with a standardized approach to maintaining cerebral oxygenation. This regimen was associated with a significant reduction of time spent with cerebral oxygenation below 55%, but serial cranial ultrasound studies and MRI at term equivalent age did not show any difference in severity of injury in monitored and control infants. However, it has been suggested that the incidence of intermittent hypoxia in extremely low-birth-weight infants progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks 6 to 8, raising the possibility that longer-term cerebral monitoring may be useful. This timing is interesting because some clinical, imaging, and neuropathological data suggest that the first days and weeks of life are critical, concerning the timing of cerebral white matter injury (see earlier) . Overall, while the use of continuous NIRS monitoring of cerebral oxygenation is promising, there is not yet sufficient evidence from outcome-based clinical trials to recommend its routine use.

Hyperoxia.

Although hypoxemia is serious and requires prompt reaction, overreaction also may be deleterious if hyperoxia is produced (see Table 16.15 ). The latter may lead to white matter or neuronal injury . Experimental studies also show that hyperoxia can lead to cerebral white matter injury similar to PVL (see Chapter 15 and later). Moreover, the neuropathological data reviewed in Chapter 14 suggest a role for hyperoxia in the genesis of a specific pattern of neuronal injury, pontosubicular necrosis. In addition, the possibility that hyperoxia may contribute to neuronal and white matter injury by causing a reduction in CBF must be considered. Reductions of CBF of 20% to 30% were shown with hyperoxia in newborn puppies, although the arterial oxygen tensions (PaO ₂ ) of approximately 350 mm Hg used were very high. Notably, in human premature infants, CBF measured by xenon clearance 2 hours after birth was 23% lower in infants who were resuscitated with 80% oxygen versus infants resuscitated with room air. In view of the critical role of cerebral ischemia in the genesis of cerebral white matter injury, this apparent effect of hyperoxia requires further study, especially in view of the recent studies concerning oxygen levels in resuscitation (see earlier).

Finally, although the cause of ROP is now recognized to be complex, hyperoxia remains an important factor. Nevertheless, the use of lower oxygen levels in preterm infants to reduce the risk of retinopathy of maturity remains an area of active research. In a recent meta-analysis, lower oxygen saturation targets did reduce the risk of ROP, but were also associated with higher mortality. The issue of recommended oxygen saturation target range was discussed earlier.

Is the Optimal Oxygen Saturation in Premature Infants Age-Dependent?

Recent experimental studies raise the question of whether the identification of optimal oxygen tension for premature infants depends not only on the absolute value but also the postnatal age of the infant. Thus at birth the transition from intrauterine placental to postnatal pulmonary oxygenation results in a drastic increase in brain oxygenation. This abrupt increase in oxygenation leads in experimental models to a diminution in brain expression of the hypoxia-inducible factor, HIF 1α/HIF 2α genes. Among the results of the latter is an increase in Wnt signaling and a decrease in VEGF expression, unlike the normal physiological situation with lower oxygen tension in fetal brain during pregnancy. These molecular events result in a diminution in angiogenesis , particularly in periventricular vessels, which are the last to mature in developing white matter. The anatomical consequences are periventricular vascular underdevelopment and local hypoxia-ischemia with the propensity to development of focal periventricular necrosis and cyst formation , that is, typical cystic PVL. (Note that this mechanism does not involve oxidative stress which, as described in Chapter 15 , appears to be important in a neonatal rodent model of hyperoxia-induced PVL.) Later, under conditions of hypoxia, as can occur in the postnatal period because of pulmonary, cardiac, and other neonatal complications, there is upregulation of HIF 1α/HIF 2α and Wnt signaling that leads to arrest of pre-OL maturation diffusely in cerebral white matter . The result of the pre-OL maturation failure, of course, would be hypomyelination, the hallmark of the diffuse component of PVL, as observed in both clinical and experimental studies (see earlier and Chapter 14 ). Accompanying upregulation of VEGF leads to enhancement of angiogenesis and thereby a decline in propensity to periventricular cystic lesions. (The similarities of this pathophysiology to ROP are apparent, wherein the initial relative hyperoxia leads to diminished retinal angiogenesis and, as a result, retinal hypoxia-ischemia, with the latter then resulting in retinal injury and excessive angiogenesis.) The implications for management of the premature infant are that hyperoxia should be avoided, especially in the early postnatal period. Indeed, it has been postulated that “restraint in using high Fi0 ₂ with careful monitoring of arterial oxygen saturation by pulse oximetry might have contributed to the decline of cystic PVL observed over the last decades.” Whether a graded postnatal increase in Fi0 ₂ levels from early to later in the postnatal period would be appropriate management for the sick premature infant is an important question, based on the experimental data just described. More data are needed on these critical issues.

Hypercarbia.

Marked elevations of PaCO ₂ are particularly dangerous in such infants because of the resulting increase in tissue PCO ₂ and consequent worsening of intracellular acidosis in brain ( Table 16.17 ). Perhaps more important than the metabolic effects and worsening of tissue acidosis are the vascular effects of hypercarbia. Thus hypercarbia results in an impairment of cerebrovascular autoregulation and, as a consequence, a pressure-passive circulation (see Chapter 13 ). In one study of 43 ventilated preterm infants in the first week of life, a progressive loss of vascular autoregulation was observed with PaCO ₂ values of 45 mm Hg or greater. As noted previously concerning hypoxemia, with hypercarbia the infant becomes especially vulnerable to ischemic cerebral injury with decreases in arterial blood pressure. Moreover, because of the potent vasodilatory effect of hypercarbia, CBF may increase and may cause a risk of hemorrhage in vulnerable capillary beds (e.g., germinal matrix and thereby intraventricular hemorrhage). These adverse effects with marked hypercarbia should be contrasted with the apparent beneficial effects of mild hypercarbia during hypoxia-ischemia (see later).

Related posts:

Prosencephalic Development Encephalopathy of Prematurity: Pathophysiology Neonatal Seizures Brain Tumors and Vein of Galen Malformations Bilirubin Preterm Intraventricular Hemorrhage/Posthemorrhagic Hydrocephalus

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