OBJECTIVE. We have previously described patterns of neonatal brain injury that correlate with global cognitive and motor outcomes. We now examine, in survivors of neonatal encephalopathy (presumed secondary to hypoxia-ischemia) without functional motor deficits, whether the severity and neuroanatomical involvement on neonatal MRI are associated with domain-specific cognitive outcomes, verbal and performance IQ, at 4 years of age.
METHODS. In this prospective study, neonatal MRIs of 81 term infants with neonatal encephalopathy were scored for degree of injury in 2 common patterns: watershed distribution and basal ganglia distribution. Follow-up evaluation at 4 years of age by examiners blinded to clinical history and MRIs included a 5-point neuromotor score and the Wechsler Preschool and Primary Scale of Intelligence–Revised. In 64 subjects with no functional motor impairment, test of trend was used to examine the association of ordered watershed-distribution and basal ganglia-distribution MRI scores with mean verbal and performance IQ.
RESULTS. Lower verbal and performance IQs were seen with increasing degree of injury on both watershed-distribution and basal ganglia–distribution scales in univariate analyses. When each MRI pattern score was adjusted for the other, only the association of decreasing verbal IQ with increasing watershed-distribution injury remained significant. A suggestion of decreasing verbal IQ with increasing basal ganglia–distribution injury was also seen in the multivariate model, whereas no association was seen between performance IQ and severity of injury in either MRI pattern.
CONCLUSIONS. In survivors of neonatal encephalopathy without functional motor deficits at 4 years of age, an increasing severity of watershed-distribution injury is associated with more impaired language-related abilities.
- brain hypoxia-ischemia
- magnetic resonance imaging
- intelligence tests
Hypoxic-ischemic encephalopathy, occurring in 1 to 6 of every 1000 live term births, accounts for a substantial proportion of neonatal brain injury representing a major cause of neurodevelopmental disability.1,2 Despite this, predicting outcomes after neonatal encephalopathy (a term used in this article to refer to the condition of brain injury after presumed neonatal hypoxic-ischemic insult) remains a significant challenge.
Large variation in definitions of hypoxia-ischemia across studies has resulted in wide-ranging estimates of outcome (as reviewed by Dilenge et al3 and van Handel et al4). To improve accuracy and precision in identifying neonatal (hypoxic-ischemic) encephalopathy, MRI is increasingly applied to quantify the degree of brain injury and to identify the specific brain regions involved.5–8 Hypoxia-ischemia in newborns typically results in 1 of 2 characteristic patterns of brain injury: (1) a watershed-distribution (WS) pattern involving intervascular boundary-zone white matter, plus cortical gray matter when severe, and (2) a basal ganglia-distribution (BG) pattern involving deep gray nuclei, hippocampi, and perirolandic cortex, with additional cortical involvement when severe.5,9 Barkovich et al5 developed an MRI scoring system for these patterns of injury. Using such a system allows for a more direct examination of the association between brain structure and behavioral outcomes. In a previous study by our group,10 injury predominantly in the BG pattern was associated with the most impaired motor and general cognitive outcomes at 30 months of age, whereas injury predominantly in the WS pattern was often associated with cognitive deficits without motor deficits. Like the majority of studies of outcomes after neonatal encephalopathy,6,8,11,12 this study evaluated cognition in terms of the presence or absence of global cognitive impairment (ie, “mental retardation”). Although providing valuable information, this approach may overlook relatively isolated impairments in specific cognitive domains. The few studies that have examined specific cognitive domains have identified language and perceptual-motor skill deficits,11,13–17 even in the setting of normal overall cognition. To our knowledge, no studies to date have examined the association between domain-specific cognitive functions and the underlying neuroanatomical regions injured in perinatal hypoxic-ischemic brain injury.
In the current study, we examined the relationship between neuroanatomic extent and severity of neonatal brain injury and future verbal and nonverbal cognitive abilities. To do so, we asked whether the severity and pattern of injury on neonatal MRI are associated with Wechsler Preschool and Primary Scale of Intelligence–Revised (WPPSI-R) verbal IQ (VIQ) and performance IQ (PIQ) scores at 4 years of age. Recognizing that assessment of cognition by neuropsychological testing is influenced by neuromotor dysfunction, we evaluated only subjects with no functional motor impairment. Because normal language function relies on anterior and posterior cortex and the underlying white matter connections, we hypothesized that VIQ scores would correlate negatively with degree of WS pattern injury. Alternatively, we hypothesized that PIQ scores would correlate negatively with degree of BG pattern injury, because of expected executive, working memory, and visuospatial impairment from striatal, hippocampal, and thalamic injury.
The present study included all eligible participants from a previously-described ongoing prospective cohort study of infants at risk for hypoxic-ischemic brain injury, including subjects enrolled from study initiation in 1994–2003.18 The protocol for the ongoing study was approved by the Committee on Human Research at the University of California, San Francisco, and subjects were studied only after voluntary informed consent was obtained from the parents. A cohort of 163 infants was derived from screening 5562 consecutive term neonates born in or transferred to the University of California, San Francisco NICU (Fig 1). All enrolled participants had 1 or more of the following markers of hypoxia-ischemia: (a) 5-minute Apgar score of ≤5; (b) umbilical artery cord blood pH <7.1; (c) umbilical artery base deficit −10 or less; or (d) clinical brain dysfunction (defined as abnormal tone, feeding, alertness, respiratory status, or reflexes). An infant was excluded for any of the following: (1) evidence of in utero or perinatal infection; (2) major anomalies of the brain or other major organ systems; or (3) evidence of congenital metabolic disease. These broad criteria were chosen to include newborn infants with a wide range of injury and of neurodevelopmental outcomes, while including some marker of hypoxic-ischemic encephalopathy.19 Each cohort participant had a brain MRI obtained during the first 2 weeks of life. Of subjects enrolled in the cohort, 27 were excluded for lack of a neonatal-acquired MRI. Subjects were excluded from the current study if MRI showed evidence of focal infarction because of different etiology and specific motor and cognitive outcomes of neonatal stroke. All participants underwent a 4-year follow-up evaluation, including a standardized neurologic examination and neuropsychological evaluation. Participants were excluded from the current study if neurologic examination revealed functional motor impairment at 4 years old (neuromotor score ≤3, see below).
A neuroradiologist (Dr Barkovich) blinded to the participants' clinical condition scored each neonatal MRI on 2 scales that rate degree of injury in 2 common patterns (described in detail previously5): WS and BG. The severity of injury in the WS pattern was scored from 0 to 5, ranging from normal, to focal infarction, through increasing extent of white matter and cortical injury (Table 1); and the severity of injury in the BG pattern was scored from 0 to 4, ranging from normal deep gray matter through increasing extent of deep gray matter and maximally including cortical gray matter injury (Table 2). The inter-observer reliability of MRI scores in this cohort was previously reported with a kappa of 0.85,10 and the intraobserver reliability of MRI scores in this cohort was reported previously as ranging from a kappa value of 0.85 to 1.0 (varying by MRI sequence).5
Four-Year Clinical Evaluation
The neuropsychological evaluation consisted of the WPPSI-R, administered by a psychologist blinded to the child's neonatal course, neurologist evaluation, and imaging. The WPPSI-R provides age-normed scaled VIQ and PIQ scores (mean ± SD: 100 ± 15 in typical children). The lowest possible formal scores are VIQ of 46 and PIQ of 45. VIQ and PIQ scores were obtained for each participant at 4 years of age. For the 1 subject in the final cohort whose language was too impaired to administer the VIQ, a “minimum score” of 1 less than the lowest possible formal score was assigned (ie, VIQ = 45).
The neurologic examination was performed by a pediatric neurologist blinded to the neonatal course, neuroimaging, and neuropsychological evaluation results. The neurologist scored neuromotor outcome using a validated neuromotor score (NMS) from 0 to 5 (Table 3). 19
Performance on the WPPSI-R can be influenced by pure neuromotor dysfunction (pointing and oromotor-dependent verbal responses for VIQ subtests; manual dexterity, and speed for PIQ subtests). To understand the relationship between injured brain structures and cognitive domain-specific function, it was important to control for functional motor impairments that may confound this relationship. Subjects were excluded from the current study if they had an NMS ≥3, implying functional motor impairment (identifiable weakness and/or cranial nerve dysfunction).
Data Analysis/Statistical Methods
Unadjusted IQ–MRI Score Associations
Univariate linear regressions were used to evaluate the unadjusted association between each IQ score (VIQ and PIQ) and each MRI pattern scores (WS and BG scores). Because WS and BG scores are based on ordinal scales, we were most interested in a trend in mean VIQ or PIQ scores across levels of WS or BG score. We therefore used the “test for trend” to assess for this type of departure from the null hypothesis of no association.
Adjustment for the Degree of Brain Injury in Other MRI Pattern
Correlation was expected between degree of WS injury and degree of BG injury (as both are thought to correspond to degree of hypoxia-ischemia experienced) and was confirmed to exist in this study. This correlation suggests the potential for confounding effect of each MRI-pattern (WS or BG) injury score on the association between an IQ score and the other MRI-pattern injury score (ie, an apparent causal relationship between 1 MRI-pattern score and an IQ score may, in fact, be because of injury in the other MRI pattern). To control for this, we used multiple linear regression models that included both BG score and WS score as predictors of the IQ score. These models yielded estimated mean VIQ and PIQ scores at each level of WS score or BG score, adjusted for the complementary MRI-pattern score. Test for statistical significance was performed using the test for trend across levels of WS score and BG score.
From the originally enrolled cohort, 136 subjects were studied with MRI (Fig 1). Sixteen subjects died before the age of 4, and 39 missed their 4-year follow-up evaluation or have been lost to study follow-up. Four-year clinical follow-up evaluation was completed by 81 subjects at the time of this study. No difference was found between distribution of WS and BG scores in subjects who missed the follow-up appointment compared with those who completed the 4-year follow-up (Kruskal-Wallis test: WS, P = .9; BG, P = .6). Of the 81 subjects, 1 was uncooperative with WPPSI testing. Seven of 81 subjects were excluded from this study because of focal strokes identified on neonatal MRI. Of the remaining eligible participants, 9 had NMS scores ≥3, leaving 64 participants for inclusion in the current study. PIQ was measured in all 64, and VIQ was measured in 63 (VIQ not valid for 1 participant for whom appropriate interpreter was not available; see Fig 1).
Of the 9 participants excluded because of NMS score representing “functional motor impairment,” all had the maximum NMS score of 5, indicating spastic quadriparesis plus cranial nerve abnormality. These subjects had the highest MRI pattern scores, such that the highest BG score (4) and the highest WS score (5) were comprised only of these subjects. Of these 9 subjects, 7 were too impaired (cognitively and/or motorically) for administration of the VIQ; 1 had a VIQ of 73 and 1 had a VIQ of 91. Eight subjects were too impaired for administration of the PIQ; 1 had a PIQ of 76.
The final cohort was comprised of 64 participants, 35 (55%) of whom were male. Mean (±SD) for VIQ was 96 (±21) and for PIQ was 101 (±17). One (1.6%) subject received the VIQ “minimum score” of 45. Six (9%) had a VIQ of <70, 14 (22%) had a VIQ of 70 to 84, and 43 (67%) had a VIQ of ≤85, whereas 1 had no VIQ measured. Clinical characteristics of the cohort, divided into 3 groups by VIQ score, are provided in Table 4. Statistically significant differences between the groups were only seen for median PIQ score (P < .0001): children in the middle and lowest VIQ groups had median PIQs 21 and 22 points lower than those in the highest VIQ group. In this cohort with no functional motor impairment, WS scores ranged from 0 to 4 (none with 5; subjects with WS score of 1 excluded). BG scores ranged from 0 to 3 (none with 4; Fig 2).
In the 4 unadjusted (univariate) analyses, lower VIQs and lower PIQs were associated with increasing degree of injury on both WS and BG scales (P ≤ .05, all 4 analyses). Range of estimated mean VIQs was 107 to 82 across WS scores and 102 to 79 across BG scores. Range of estimated mean PIQs was 109 to 96 across WS scores and 105 to 86 across BG scores.
When the association between the MRI pattern score and the VIQ or PIQ score was adjusted for the complementary MRI pattern score (Fig 3), only the association of decreasing VIQ with increasing WS injury remained statistically significant (P = .01; range of estimated mean VIQs across WS scores: 105–84). The test for trend suggested that VIQs decrease with increasing BG injury as well, although this was not statistically significant (P = .06; range of estimated mean VIQs across BG scores: 100–81). No association was seen between PIQ and severity of injury in either MRI pattern (WS: P = .24, range of estimated mean PIQs: 108–97; BG: P = .15, range of estimated mean PIQs: 105–86).
In this prospective study, we examined the association of MRI patterns of brain injury in neonatal encephalopathy presumed secondary to hypoxia-ischemia with verbal (VIQ) and nonverbal (PIQ) cognitive outcomes at 4 years old in children with no functional motor impairment. Our results demonstrated an independent association between degree of WS injury in the neonatal period and future verbal abilities measured by the WPPSI-R. The association identified between degree of BG injury and verbal abilities was not statistically significant, suggesting a less robust, if truly existent, association.
Studies of neonatal hypoxic-ischemic encephalopathy using the traditional biochemical and/or clinical markers have yielded mixed results with a broad range of possible sequelae in the setting of moderate encephalopathy,3,4 suggesting significant heterogeneity of this group. Studies incorporating prospective neuroimaging10,12 have begun to show that pattern of brain injury, and not just severity, is important in determining future domain (motor versus cognitive) impairment. Viewing cognition in mostly general and dichotomous terms (eg, “mental retardation” versus “no mental retardation”)6,8,11,12 has likely contributed to the often-ambiguous results obtained about those with a history of moderate encephalopathy. The current study is, to our knowledge, the first prospective study of neonatal encephalopathy because of presumed hypoxic-ischemia to show that the distribution of brain injury is also important in determining the specific pattern of future cognitive dysfunction.
Of the relatively small number of studies of specific cognitive outcome patterns in this condition, a domain in which isolated cognitive dysfunction has been identified is language.14,16,20 D'Souza and colleagues14 found speech and language deficits in approximately one third of survivors of severe perinatal asphyxia in the setting of normal general intellect. In subjects with a history of moderate encephalopathy, Marlow et al16 identified lower scores in language and verbal memory tests compared with controls. Our findings provide evidence that such domain-specific cognitive function may reflect underlying brain structures injured, specifically the white matter and cortical injury seen in the WS pattern of injury.
Previous studies examining specific cognitive domains after presumed hypoxic-ischemic neonatal brain injury have also identified deficits in nonlanguage domains.13,16,17 In the current study, no association was identified between PIQ (which includes subtests involving visuospatial knowledge, visual memory, and executive function) and either BG or WS injury. This leaves the question of what type of brain injury leads to deficits in the nonverbal cognitive abilities measured by PIQ? The presence of associations in the unadjusted analyses with BG and WS, but lack of an independent association with either pattern of injury, suggests that it is the interaction of these injury patterns that results in the nonverbal cognitive deficits. In other words, PIQ is mediated by the degree of injury in multiple areas, including areas involved in both patterns of injury. This could provide a neuroanatomic explanation of the finding of Marlow et al16 of visuospatial impairment in subjects with more severe, but not moderate, encephalopathy, compared with controls.
One limitation to the current study is the relatively imprecise nature of the VIQ and PIQ scores, each comprising multiple subtests requiring interrelated cognitive abilities. More detailed neuropsychological testing of specific cognitive domains (eg, verbal memory, vocabulary production, and sentence comprehension) could provide even greater information about the spectrum of cognitive deficits associated with different neuroanatomic patterns of perinatal brain injury.
The aim of the current study was to understand the relationship between injured brain structures and cognitive domain-specific function, independent of neuromotor function. Due to the small number of subjects with functional motor impairment, their severity of impairment (mostly precluding neuropsychological testing), and their limited variability of MRI pattern scores, statistical analysis incorporating this group was felt to provide inaccurate results. To address the question of association between specific brain regions injured and domain-specific cognitive outcomes, we therefore limited our study to subjects with no functional motor impairment (NMS < 3). Given this, our findings must be interpreted with caution in children with functional motor deficits.
Interestingly, in children with no functional motor impairment we found no clear association between degree of BG injury and verbal or nonverbal cognitive outcomes. When examining the entire cohort (ie, those with and without motor impairment) at 30 months, we have previously shown10 that injury predominating in the BG pattern was associated with the worst cognitive and motor outcomes at 30 months. In contrast, in the whole cohort, those with mostly WS pattern of injury had cognitive impairments less severe than those with the BG pattern and did not have motor impairments. These previous findings are still in keeping with what we are describing here in those without motor impairment. Poor cognitive outcomes with BG injury seen in the previous study may not be attributable to basal ganglia, thalamic, or perirolandic injury given the occurrence of more diffuse cortical injury in the most extreme BG pattern (Table 2), present only in those with functional motor impairment at 4 years old. In addition, given the high co-occurrence of WS injury with BG injury, the presence of WS injury in those with predominantly BG pattern injury in the previous study may have contributed importantly to the severe cognitive impairments in these children. Therefore, when we examined only subjects without motor deficits and adjusted for severity of WS injury in this study, the severity of BG injury was not significantly associated with the severity of cognitive deficits. In addition, some of the apparent “severe cognitive impairment” seen when BG injury predominates may reflect inability to assess cognition accurately in the face of severe neuromotor disability.
Our current findings of an independent association between degree of WS injury and future language-related deficits demonstrate the use of neuroimaging to identify neuroanatomic distribution of brain injury in neonatal hypoxic-ischemic encephalopathy and their relation to domain-specific cognitive outcomes. Future studies that examine the association between perinatal brain injury distribution and cognitive outcome patterns are needed, including examination of these associations in children with motor impairment and examination with more detailed measures of specific cognitive domains. Such studies will hopefully lead to better ability to predict cognitive outcomes after neonatal encephalopathy, a worthy goal as we enter an era of experimental treatments.
This work was supported by grant UL RR024131-01 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Information on NCRR is available at www.ncrr.nih.gov Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. This work was also supported by the National Institutes of Health (NS35902). Dr Steinman is supported by the NINDS Neurological Sciences Academic Development Award (NS01692). Mr Miller is a Canadian Institutes of Health Research Clinician Scientist and Michael Smith Foundation for Health Research Scholar.
We thank Rita Jeremy, PhD, and Agnes Bartha, MD, for work on this study and Hannah Glass, MD CM, FRCP(C), MAS, and the University of California San Francisco Master's Program in Clinical Research Seminar for helpful discussion.
- Accepted July 15, 2008.
- Address correspondence to Kyle J. Steinman, MD, MAS, University of California, Division of Child Neurology, 350 Parnassus Ave, Suite 609, San Francisco, CA 94117. E-mail:
The views in this article are those of the authors and do not necessarily represent the official view of the National Center for Research Resources or the National Institutes of Health.
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Variable definitions of neonatal encephalopathy have yielded wide-ranging estimates of its neurodevelopmental outcomes. Neuroimaging studies show that pattern of neuroanatomic involvement helps determine degree of future cognitive impairment. These studies have only assessed global cognitive ability, overlooking isolated impairment in specific cognitive domains.
What This Study Adds
By identifying an association between watershed-distribution injury and future language-related deficits, this is the first prospective study of neonatal encephalopathy to show that neuroanatomical distribution of brain injury has the potential to predict future domain-specific cognitive dysfunction.
- ↵Volpe JJ. Neurology of the Newborn. Philadelphia, PA: W.B. Saunders; 2001
- ↵Dilenge ME, Majnemer A, Shevell MI. Long-term developmental outcome of asphyxiated term neonates. J Child Neurol.2001;16 (11):781– 792
- ↵Barkovich AJ, Hajnal BL, Vigneron D, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol.1998;19 (1):143– 149
- ↵D'Souza SW, McCartney E, Nolan M, Taylor IG. Hearing, speech, and language in survivors of severe perinatal asphyxia. Arch Dis Child.1981;56 (4):245– 252
- Moster D, Lie RT, Markestad T. Joint association of Apgar scores and early neonatal symptoms with minor disabilities at school age. Arch Dis Child Fetal Neonatal Ed.2002;86 (1):F16– F21
- ↵Marlow N, Rose AS, Rands CE, Draper ES. Neuropsychological and educational problems at school age associated with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed.2005;90 (5):F380– F387
- ↵Barkovich AJ, Baranski K, Vigneron D, et al. Proton MR spectroscopy for the evaluation of brain injury in asphyxiated, term neonates. AJNR Am J Neuroradiol.1999;20 (8):1399– 1405
- Copyright © 2009 by the American Academy of Pediatrics