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Encephalopathy of Prematurity Includes Neuronal Abnormalities

Department of Neurology
Children’s Hospital and Harvard Medical School
Boston, MA 02115

Abbreviations: PVL, periventricular leukomalacia

The dominant encephalopathy of premature infants is considered generally to involve principally white matter.¹ Periventricular leukomalacia (PVL) is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. Injury to premyelinating oligodendrocytes appears to be a feature of the diffuse lesions,² although the nature and extent of this cellular injury require additional study. This diffuse, noncystic white matter injury without focal necrosis is much more common than classic PVL. Results of neonatal imaging studies indicate that classic PVL with focal necrotic/cystic lesions occurs in 3% to 5% of very low birth weight premature infants (<1500 g), whereas the more diffuse noncystic lesions are demonstrable, on average, in 20% to 50%, depending on the imaging modality and the definition of abnormality (see ref 1 for review).

Despite the longstanding emphasis on cerebral white matter among premature infants, numerous recent MRI studies of such infants at term and later ages suggest strongly that cerebral neuronal structures are abnormal frequently (see below). These observations are of particular importance because of the high incidence (50%) among survivors of prematurity of subsequent cognitive deficits without prominent motor deficits, a combination classically attributed in neurology to neuronal abnormalities rather than white matter abnormalities. The report by Lodygensky et al³ published elsewhere in this issue is focused on abnormal gray matter development, defined with volumetric MRI, among premature infants studied at 8 years of age and is highly relevant to the issue of neuronal abnormalities among premature infants. In addition, this work addresses the effect of postnatal hydrocortisone administration on subsequent structural and functional brain development. The focus on hydrocortisone is presented briefly next, and the emphasis on the broader effects of prematurity on central nervous system neuronal structures follows.

	POSTNATAL GLUCOCORTICOIDS AND SUBSEQUENT BRAIN DEVELOPMENT

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Glucocorticoids administered postnatally to premature infants are recognized widely to lead to a decrease in the incidence of bronchopulmonary dysplasia and to be associated with numerous short-term, adverse, systemic effects.^4,5 Still more concerning, long-term, adverse, neurologic effects have been identified.^6–8 Consistent with the neurologic sequelae, a recent study of a small group of premature infants treated with high-dose dexamethasone showed, at term, a significant reduction in cerebral cortical gray matter volume, quantitated with three-dimensional volumetric MRI.⁹ Because nearly all studies of the adverse neurologic effects of postnatal glucocorticoids involved dexamethasone, a compound shown experimentally to impair neuronal development and potentially to enhance neuronal injury,⁵ the possibility of less or no neurotoxicity with administration of other glucocorticoids has been raised. The report by Lodygensky et al³ suggests that hydrocortisone could be such an agent. Those investigators studied 60 preterm infants, at a mean age of 8 years, with quantitative MRI. Twenty-five had been treated with hydrocortisone as newborns (mean age at onset: 18 days; dose: 5 mg/kg per day for 1 week; total duration after taper: 26 days), and 35 had not been treated. At 8 years of age, cerebral cortical gray matter, white matter, and hippocampal volumes did not differ between the 2 groups, and Wechsler Intelligence Scale for Children scores were similar.

Why might hydrocortisone therapy not be associated with long-term neurologic deficits, whereas dexamethasone is associated with such deficits? One possible contributing factor is that hydrocortisone in brain binds preferentially to the mineralocorticoid receptor, whereas dexamethasone binds preferentially to the glucocorticoid receptor.^10,11 Activation of the glucocorticoid receptor leads to adverse neuronal effects.^12,13 A possible contributory deleterious role involving excitotoxic effects of sulfites in the dexamethasone preparation was suggested by in vitro studies.¹⁴ Despite these interesting observations, however, the mechanisms of the neurologic effects of dexamethasone among premature newborns are likely still more complex and remain to be clarified. Although it is possible that the pharmacologic doses of hydrocortisone used in the current study³ may be preferable to dexamethasone, greater experience is required to ensure that the former steroid regimen is completely safe. Moreover, although hydrocortisone, used earlier and in lower doses than in the current study, appeared to lead to beneficial pulmonary effects,¹⁵ gastrointestinal complications may preclude routine use.⁴

	PREMATURITY AND CEREBRAL NEURONAL ABNORMALITIES

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Premature Infants Studied in Childhood and Adulthood
Quantitative MRI studies of cerebral gray matter structures of premature infants evaluated at term and later in childhood have provided strong evidence of neuronal abnormalities. Indeed, the findings suggest that such abnormalities may be common important features of the neuropathologic basis of the subsequent cognitive disabilities among such infants.

Advanced MRI techniques applied to children and adults who were born prematurely led to the seminal observations of distinct abnormalities in cerebral gray matter.^3,16–21 Decreased cerebral cortical gray matter volumes were shown most consistently.^3,16–21 In the report in the current issue of Pediatrics, 61 formerly premature infants studied at 8 years of age showed 2% to 3% decreases in cerebral cortical gray matter volumes.³ The difference remained significant when the 12 infants with overt PVL and/or severe intraventricular hemorrhage were excluded. Importantly, the cortical gray matter deficit was related inversely to birth weight, ie, the smallest infants exhibited the largest volumetric deficits subsequently.³ Regional differences in the cerebral cortical volumetric deficits were shown, with the most pronounced decreases occurring generally in sensorimotor, parieto-occipital, temporal, and hippocampal cortices.^16–18,21 A slight increase in cortical gray matter volumes of frontal and parietal lobes was observed in a recent study²¹ and raised the possibility to the authors that a disturbance in a so-called regressive developmental event (eg, apoptosis or pruning of neuronal processes or synapses) could have occurred. In addition to decreases in cerebral cortical volumes, decreases in volumes of deep nuclear structures (eg, basal ganglia or thalamus, usually studied in combination) have been documented.^17,19–22 Functional significance of these various neuronal disturbances among formerly premature infants is suggested by correlations of the cortical and/or deep nuclear deficits with abnormal cognitive measures.^{16,17,19,21,23}

Therefore, these informative MRI studies performed after the neonatal period have made the key observation of cerebral cortical and deep nuclear volumetric deficits for substantial proportions of surviving premature infants. Whether these deficits are related to direct injury to neurons and/or to white matter incurred in the neonatal period is not clear from these reports. The premature infants who were studied years later with volumetric MRI were evaluated in the neonatal period with imaging modalities (eg, ultrasonography) that are ineffective generally for detection of cortical neuronal or noncystic white matter lesions. Readily detected, overt, necrotic/cystic PVL was a very unusual finding. Therefore, this important corpus of work leaves unresolved the questions related to the mechanisms of the neuronal volumetric deficits, such as whether they are primary or secondary, destructive or dysgenetic (see below).

Premature Infants Studied at Term Equivalent
Advanced MRI techniques applied to premature infants as early as term equivalent support the idea derived from studies performed at later ages that cerebral neuronal abnormalities are important features of the neuropathologic basis of prematurity. In general, the deficits appear more marked among infants than among children and adults.

The first clear indication from advanced MRI studies of disturbances in the cerebral cortex among premature infants came from the study by Inder et al.²⁴ In comparison with cerebral cortical gray matter volumes among healthy term infants, a 28% reduction in cortical gray matter was observed at term for 10 premature infants with earlier MRI evidence of PVL, defined as either cystic (n = 5) or noncystic (n = 5) white matter lesions. (The small number of infants with white matter lesions precluded comparative analyses of cortical gray matter reduction in relation to cystic versus noncystic white matter lesions.) Notably, in this small series, the 10 infants without PVL exhibited no deficit in cerebral cortical gray matter volume, compared with healthy term infants. A small (n = 14) later series of premature infants without overt parenchymal lesions showed at term a quantitative deficit in the complexity of cortical folding,²⁵ raising the possibility of a disturbance of cerebral cortical development in the absence of major white matter injury. Apparent deficits in the volumes of several cerebral cortical regions, especially the parieto-occipital cortex, were identified among 10 premature infants studied at 35 weeks’ postconceptional age by Peterson et al.²⁶ Only 2 of those infants were reported to have "PVL," as determined with "clinical MRI." In that interesting report, however, the premature infants at 35 weeks were compared with term infants; the period from 35 weeks to 40 weeks of gestation involves normal rapid increases in cerebral cortical gray matter volume.²⁷ The most decisive demonstration of disturbances of cerebral cortical gray matter volume among premature infants as early as term equivalent was obtained recently in a study of 119 consecutively studied premature infants and 21 normal term infants.²⁸ Infants with MRI-defined white matter injury had 33% lower cerebral cortical gray matter volume, consistent with the earlier findings by Inder et al²⁴ in a much smaller cohort. However, unlike the earlier report of 10 preterm infants with white matter injury, in the larger study of 119 infants, 80% of the infants with white matter injury exhibited noncystic disease. Notably, the 98 infants free of white matter disease in MRI scans exhibited a 20% lower cerebral cortical gray matter volume, compared with the term infants, although this effect did not reach statistical significance in multivariate analysis. In addition, overall the volume of deep nuclear structures was 22% lower among the preterm infants than among the term infants, and this significant volumetric deficit was greatest among the most immature infants. Moreover, the neuronal deficits in both cerebral cortex and deep nuclear structures correlated with moderate/severe neurodevelopmental disabilities at 1 year of age.²⁸

Taken together, the volumetric findings at term equivalent show pronounced deficits in cerebral cortical and deep nuclear gray matter volumes. The deficits are unequivocal among infants with white matter disease that is not necessarily severe. Whether less-pronounced neuronal deficits are also present among infants with no MRI-demonstrable white matter disease remains to be clarified, but available data are suggestive.

	NEUROPATHOLOGIC BASIS FOR DECREASED CEREBRAL CORTICAL AND DEEP NUCLEAR VOLUMES IN PREMATURITY

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Delineation of the neuropathologic substrate underlying the deficits in cerebral cortical and deep nuclear volumes defined with quantitative MRI at term equivalent and later in childhood is critical to help define the mechanisms leading to these deficits. The cellular elements of particular concern are cerebral cortical neurons, underlying subplate neurons, descending and ascending axons in white matter, and deep nuclear neurons, especially those of the thalamus. These elements represent an interacting cortical-thalamic unit, as described below. The key question for premature infants is whether one or more of the components of this neuronal-axonal unit sustain changes that are destructive or dysgenetic, or both.

Neuropathologic studies of cerebral cortical or thalamic neuronal structures among premature infants are relatively few. Earlier work indicated that neuronal injury may accompany severe forms of PVL.^29–33 However, because little information is available for the premature population in general, ie, without or with white matter injury, our group conducted a detailed analysis of the neuropathologic features of 41 premature infants who underwent autopsies at Children’s Hospital Boston between 1997 and 1999.³⁴ Although neuronal necrosis and loss were relatively common among infants with focal necrotic and/or cystic PVL, definite neuronal injury was very uncommon among infants with noncystic white matter injury and was rare among those with apparently normal white matter (by conventional histologic evaluations). This observation suggests that direct neuronal necrosis and loss do not account for the volumetric deficits later identified with MRI in the large population of premature infants with noncystic white matter injury observed with neonatal imaging. These findings, however, do not rule out the possibility that sublethal neuronal injury occurs and then is followed by impairment of neuronal development (see below).

Neuropathologic evidence for axonal injury among premature infants is limited to studies of those dying with classic PVL.^35–38 Early descriptions of PVL included the observation that axonal swellings or spheroids, indicative of acute axonal injury, are present in the necrotic foci.^29,30 More extensive axonal injury around necrotic foci was detected with immunocytochemical staining for ß-amyloid precursor protein, a marker of axonal damage.^35–38 However, neuropathologic investigation of possible axonal injury in the more common noncystic white matter injury characteristic of most of the living premature infants studied with quantitative volumetric MRI is lacking. Therefore, the role of this key component of the neuronal-axonal unit in the genesis of the cortical and/or thalamic volumetric deficits is a key topic for future work.

The pivotal intermediary neuronal component in the cortical-thalamic unit is the subplate neuron, the only neuronal element of developing cerebral white matter. This component is central to both cortical and thalamic development (see below). The neuropathologic changes in this white matter neuronal constituent among human premature infants have not been delineated. Subplate neurons contain excitatory amino acid receptors and were shown recently, in a developing animal model, to be selectively vulnerable to hypoxia-ischemia.³⁹ Because hypoxia-ischemia and excitotoxicity are considered important in the pathogenesis of white matter injury¹ and the presence of white matter injury is associated with the cortical and deep nuclear volumetric deficits, a potential role for concomitant injury to subplate neurons in this scenario is raised (see below).

Therefore, it is clear that the neuropathologic features of neuronal-axonal elements among human infants remain largely to be defined. Currently, available data indicate that neuronal and axonal injury per se is relatively common only in overt (necrotic/cystic) PVL. However, application of modern immunocytochemical techniques to detect sublethal injury to neurons and/or axons and perhaps subsequently impaired development of these structures is needed to assess the large proportion of infants without severe PVL.

	POTENTIAL MECHANISMS UNDERLYING THE RELATIONSHIP OF PREMATURITY TO NEURONAL DEFICITS

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The cerebral cortical and deep nuclear neuronal deficits defined with MRI could be related to a variety of mechanisms, in basic nature principally either destructive or developmental, or both. These potential mechanisms are discussed briefly.

For cortical and thalamic neurons, evidence of destructive disease, ie, overt neuronal necrosis, is lacking, except among infants who die with severe PVL (see above). However, the possibility of sublethal injury requires consideration. The mechanism of such injury could involve the action of reactive oxygen species generated through ischemia and inflammation.⁴⁰ Indeed, in recent preliminary neuropathologic studies of premature infants, our group showed increased immunoreactivity for products indicative of attack by reactive oxygen species in cortical neurons overlying areas of PVL.⁴¹ Whether such sublethal injury could lead to impaired neuronal development is an important question. A developmental effect on cortical and thalamic neurons also could occur secondary to interruption of afferent or efferent axonal connections. This mechanism was suggested in PVL by the anatomic studies of Marin-Padilla,³² who demonstrated distinct alterations in morphologic features and organization of neurons and neuronal processes in the cerebral cortex overlying relatively severe necrotic/cystic PVL, weeks and months after the neonatal period. Whether this apparent secondary developmental effect could occur among living infants with the less severe noncystic white matter injury is unclear.

Subplate neurons are crucial for cortical and thalamic neuronal development, and injury could lead to profound neuronal abnormalities.^42–46 Subplate neurons reach their peak abundance in human infants during the gestational period of human prematurity, particularly the period of peak vulnerability to PVL, ie, 22 to 34 weeks.^42,44 These cells serve as transient sites for connections by "waiting afferents" to the developing cerebral cortex (thalamocortical and corticortical axonal projections), may guide axons to cortical and subcortical targets, and are involved in structural and functional maturation of the cerebral cortex and the thalamus.^1,42–55 As noted earlier, in a neonatal rat model, subplate neurons exhibited selective vulnerability to hypoxia-ischemia.³⁹ The critical issue of the status of subplate neurons among human premature infants is a key topic for future research.

Axonal disturbance could have a profound impact on cortical and thalamic neuronal development through retrograde and anterograde effects and potentially thereby on the volumetric measures detected with MRI. Essentially nothing is known about the status of axons among human premature infants. To elucidate axonal development during this period, our group undertook a study of cerebral white matter, with immunocytochemical and Western blot analyses, in 46 normative cases beginning at 20 postconceptional weeks.⁵⁶ The findings were unexpected and dramatic. Although axons were clearly detectable as early as 23 weeks, specific markers indicated that these axons were clearly immature. Importantly, growth-associated protein-43, a marker of axonal growth and elongation, showed high levels of expression (four- to fivefold greater than adult levels) throughout the premature period, indicating that these immature axons are in a phase of very active development. These data appear to define the human premature period as a critical period in axonal development. It is likely that these immature axons are highly vulnerable to injurious insults (eg, ischemia and inflammation). Indeed, mature axons are known to be vulnerable to ischemia.⁵⁷ In addition, oligodendroglial-axonal interactions are critical for axonal survival, maturation, and function.^58–61 Therefore, in the diffuse component of PVL, the injury to preoligodendrocytes² could contribute ultimately to impaired axonal number or maturation, or both. Potentially supportive of a disturbance in axonal development among premature infants are diffusion-based MRI studies that show white matter abnormalities consistent with (although not specific for) impaired axonal development.^62–65 Taken together, these data raise the possibility that axonal disturbance is present among premature infants and could be related causally to deficits in cerebral cortical and deep nuclear (especially thalamic) neuronal development.

	CONCLUSIONS

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Cerebral white matter injury has long been recognized as common and serious among premature infants. However, now an exciting confluence of new and evolving data focuses our attention on the neuronal-axonal unit among such infants. Neuronal-axonal disturbance could underlie the most common type of neurologic sequelae in this population, ie, abnormalities of cognition, attention, and behavior. This disturbance occurs in its most severe form in the presence of overt cerebral white matter injury, but recent volumetric MRI data indicate that marked white matter injury is not essential for the neuronal-axonal abnormality. The encephalopathy of prematurity now appears to include both white matter and neuronal-axonal disease, and it is clearly time for us to obtain greater insights into the latter.

	FOOTNOTES

 
Accepted Feb 4, 2005.

Reprint requests to (J.J.V.) Department of Neurology, Fegan 1103, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: joseph.volpe{at}childrens.harvard.edu

No conflict of interest declared.

	REFERENCES

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