PEDIATRICS Vol. 115 No. 4 April 2005, pp. 1083-1084 (doi:10.1542/10.1542/peds.2005-0256)
COMMENTARY |
Structure Versus Function: Time Will Always Tell
Department of Pediatrics
Connecticut Children’s Medical Center
Hartford, CT 06106
Abbreviations: ELBW, extremely low birth weight • HUS, head ultrasound • CP, cerebral palsy • IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia
The article by Laptook et al1 in the March issue of Pediatrics examined clinical follow-up assessments at 18 to 22 months’ corrected age of an extremely low birth weight (ELBW) infant cohort cared for in the Neonatal Research Network Centers within the years 1995–1999. From the study cohort of 1749 infants, 84% (1473 infants) returned for follow-up assessments. The authors found that nearly 30% of those infants with a normal, early, and late head ultrasound (HUS) (performed at a mean age of 6 and 47 days, respectively) were found later to have either cerebral palsy (CP) (9.4%) and/or a low (<70) Mental Developmental Index (25.3%) on Bailey Scales of Infant Development II. All infants included in the study had a birth weight of 729 ± 134 g and a gestational age of 26 ± 2 weeks.
Multivariate analyses revealed that factors associated with subsequent CP were male gender, multiple birth, decreasing birth weight, pneumothorax, and days of mechanical ventilation.1 The same factors, with the exception of pneumothorax, were associated with a Mental Developmental Index of <70 in addition to less maternal education and having Medicaid or lack of coverage for maternal insurance. Equally important, however, is the fact that from the initial cohort of 6905 infants with a birth weight of <1000 g, one third (2378 [34.4%]) died before discharge. Of the survivors, 2006 were excluded because of intrauterine infection, major malformation syndrome, or at least 1 abnormal ultrasound. Other exclusions and lack of follow-up resulted in the final 1473 infants who met inclusion criteria comprising the report. It is clear that the vast majority (
75%) of ELBW infants will die or have readily identifiable problems early.
There are some additional important conclusions to be abstracted from the current report. The most obvious conclusion is that a normal HUS "early and late" does not exclude the possibility of CP neurodevelopmental sequelae. The authors defined a normal HUS as the absence of abnormal intraventricular or periventricular echodensity or echolucency within a normal-sized ventricular system. One weakness of the study is that the interpretation of HUSs was from each of 14 different centers and not by a central reviewer. Still, obvious abnormalities should be readily identifiable and relatively few overlooked. The notable exception is when there is a global or diffuse reduction in cerebral volume, which will likely be underappreciated with HUS. This reduction may well have significant, long-term neurodevelopmental consequences. The timing of the HUS study certainly may have an impact. All HUSs were obtained within the first 5 to 10 days for an early study and at 36 weeks’ corrected gestational age or at discharge from the nursery. These are well within the recommended neuroimaging windows suggested by the report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.2 Unfortunately, there were no long-term postdischarge imaging data for analysis. It should be remembered that cystic periventricular leukomalacia (PVL) has been identified as late as 104 days postnatally in infants whose initial studies had otherwise been normal.3 It again is unlikely, however, that a sizable fraction of the study cohort with abnormal clinical outcomes would have had identifiable neurosonographic abnormalities at an even more delayed time. The predictability of clinical outcome by use of ultrasound simply has limitations.
It is important to remember that structure and function, although interrelated, do not always equate with each other, which is particularly true when the examination of an elegant and complex organ such as the brain is performed with a rather crude analysis technique (ultrasound). Nonetheless, there are ample data to support predictable abnormal clinical outcomes with HUS findings of intraventricular hemorrhage (IVH), white-matter injury with cystic lesions, and ventriculomegaly in ELBW infants.4
More sensitive neuroimaging techniques will be required to precisely identify subtle cerebral abnormalities and predict abnormal clinical outcomes. A recent series of unselected premature infants (23–32 weeks’ gestation; mean birth weight: 1063 ± 292 g) studied with MRI at term corrected age was published recently.5 The 100 consecutive premature infants studied represented 98% of all eligible infants during the period of study. Independent, blinded, neuroradiology evaluation graded 8 specific imaging items including white-matter signal abnormality, white-matter volume reduction, cystic abnormalities, lateral ventricle sizes, corpus callosum and myelination pattern, cortical gray-matter signal abnormality, gyral maturation, and subarachnoid space size. The authors found that 20% of the infants studied had moderate to severe cerebral white-matter abnormalities after excluding grades III and IV IVH and cystic PVL. More compelling additional findings included evidence of cortical gray-matter abnormality with delayed gyral development and enlarged subarachnoid spaces in 10 of 11 premature infants of <26 weeks’ gestation. This unique pattern of global structural disturbance was seen only in ELBW infants of <26 weeks’ gestation.5 It has been postulated that the lack of cystic change in the white matter of extremely premature infants has to do with a maturation-dependent vulnerability of the developing oligodendrocyte.6 Injury more diffusely to oligodendroglial cells may, in turn, impact profoundly on later cortical gyral development and subcortical intracerebral connectivity. These subtleties in brain-imaging abnormalities are not well appreciated with HUS. The expanded capabilities of MRI will undoubtedly advance our prognostic capability. New techniques are available to assess brain chemistry with magnetic resonance spectroscopy, early brain ischemia with diffusion-weighted imagings, the mapping of white-matter pathways with diffusion-tensor imaging, and brain organization and activation with functional MRI and automated volumetric analysis.7
We again are reminded through the efforts of Laptook et al that HUS is an extremely useful and readily available tool for screening high-risk infants for identifiable cerebral abnormalities such as grades III or IV IVH, cystic PVL, and ventricular enlargement, each of which are associated with abnormal neurodevelopmental outcomes. However, more subtle microscopic and intrinsic cellular mechanistic abnormalities may be present but are unidentifiable with this tool. These underlying etiopathological abnormalities will surface in time as impaired function despite a normal HUS screening.
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FOOTNOTES |
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Accepted Feb 4, 2005.
Reprint requests to (F.J.D.) Department of Pediatrics, Connecticut Children’s Medical Center, 282 Washington St, Suite 2A, Hartford, CT 06106. E-mail: fdimari{at}ccmckids.org
No conflict of interest declared.
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REFERENCES |
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 TOP REFERENCES |
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- Laptook AR, O’ Shea TM, Shankaran S, et al. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents.
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[Abstract/Free Full Text] - Ment LR, Bada HS, Grant PE, et al. Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurological and Practice Committee of the Child Neurology Society.
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- Dammann O, Hagberg H, Leviton A. Is periventricular leukomalacia an axonopathy as well as an oligopathy? Pediatr Res. 2001;49 :453 –457[Web of Science][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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