One hundred and forty-three infants were enrolled and imaged between November 1996 and June 2003. Of these, 16 died and 77 (61% of the survivors) had complete neurodevelopmental evaluation at age four years. There was no statistical difference in demographic or clinical data between infants who had a complete neurodevelopmental evaluation at age four years compared with those who were lost to follow-up, including infant sex, birth weight and encephalopathy score (P > 0.1). Furthermore, surviving children who had a complete evaluation at age four years were no more likely than children who were lost to follow-up to have neonatal seizures (32% vs 38%, P = 0.4) or brain injury on MRI (73% vs 72%, P = 0.9).
The 16 children who died represented the severe spectrum of hypoxic-ischemic brain injury. Nine (56%) had maximal basal nuclei and watershed scores. All 16 infants had seizures (12 with severe seizures). Eleven (69%) died in the neonatal period following discontinuation of active cardiorespiratory support in the intensive care nursery.
Of the 77 surviving infants followed to age four years, 11 (14.3%) had severe neonatal seizures (composite seizure score ≥4), 14 (18.2%) had mild/moderate seizures (seizure score 1-3) and 52 (67.5%) had no seizures (seizure score 0). Of the 25 infants with seizures, all infants had clinical seizure onset prior to the third day of life (with the exception of a single infant who was paralyzed until day four of life for extracorporeal membrane oxygenation). Two infants (8%) required three or more anti-seizure medications. All of the infants with clinical seizure had an electroencephalogram, which was abnormal in 14 (56%). Recurrent electrographic seizures were present in six cases. Of the infants without clinical seizures, only one had an electroencephalogram, which was normal.
There was no significant difference in birth weight, umbilical cord or first arterial blood gas pH or base excess between the infants with severe or mild/moderate neonatal seizures when compared to those without seizures. There was no apparent difference in the percentage of male infants with seizures compared to those without (64% vs. 50%, P = 0.25). The higher rate of seizures in infants born outside our center was not significant. The lower Apgar scores in infants with seizures were also not significant. Infants with neonatal seizures were more likely to have a higher encephalopathy score (P = 0.002) ().
Clinical characteristics by seizure severity of 77 infants at risk for perinatal hypoxic-ischemic brain injury followed to age four years
The MRI pattern of hypoxic-ischemic injury differed in infants with severe seizures when compared with those with mild/moderate or no seizures (P < 0.0001, ). Of the infants with severe seizures, the basal nuclei predominant pattern was most common (54.6%). Of the infants with mild/moderate seizures, the watershed pattern of injury was most common (50.0%). Infants without seizures were also most likely to have the watershed pattern of injury (55.8%). Four infants had maximal basal nuclei and watershed scores (two with mild/moderate seizures and two with severe seizures).
Predominant pattern of injury by seizure severity in 77 infants at risk for perinatal hypoxic-ischemic brain injury followed to age four years
Of the known predictors of outcome, the severity of hypoxic-ischemic brain injury detected by magnetic resonance imaging and as measured by our scoring system was most highly associated with the cognitive outcome in this cohort. The basal nuclei and watershed scores predicted 39% of the variation in the FSIQ scores, as compared to 25% for the maximal encephalopathy score and 29% for the seizure score (all P < 0.0001).
Newborns with seizures in the setting of perinatal asphyxia had worse outcomes than infants without seizures (). In the unadjusted analysis, for each one-point increase in seizure score, there was a corresponding 6.1-point decrease in the FSIQ (95% CI −8.3 to −3.9). The infants with documented recurrent seizures on EEG had lower FSIQ scores (mean 52 versus 95, P < 0.0001). When seizures were analyzed as a categorical variable, children with severe seizures had, on average, a WPPSI-R FSIQ that was 35.5 points lower than infants without seizures (95% CI −48.8 to −22.1 points), whereas children with mild/moderate seizures had a WPPSI-R FSIQ that was 17 points lower than infants without seizures (95% CI −30 to −5). In the unadjusted analysis, the impact of seizures on the WPPSI-R Performance and Verbal IQs was similar to the effect on the FSIQ.
Full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R) at age four years by seizure severity in 77 children at risk for perinatal hypoxic-ischemic brain injury
Children with neonatal seizures were more likely to have an abnormal neurological examination (neuromotor score ≥2) at four years when compared with children with without seizures. The unadjusted odds of a neuromotor score ≥2 were 20.8 (95% CI 5.1-85.0) in children with neonatal seizures when compared to children without seizures. Abnormal neurological examination was present in 7 (63.6%) children with severe neonatal seizures, 7 (50.0%) children with mild/moderate seizures and 3 (5.8%) children without seizures.
The association between seizures and poor neurodevelopmental outcome persisted after adjusting for the severity of hypoxic-ischemic brain injury as measured by the basal nuclei and watershed scores on MRI (). In the adjusted analysis, for each one-point increase in seizure score, there was a corresponding 4.7-point decrease in the FSIQ (95% CI −7.2 to −2.2). The effect of documented recurrent seizures on EEG also persisted after adjusting for injury on MRI, with and average FSIQ that was 33.0 points lower (95% CI −50.9 to −15.0). When seizures were analyzed as a categorical variable, infants with severe neonatal seizures had average adjusted WPPSI-R FSIQ scores that were 29.7 points lower (95% CI −45.2 to −14.2 points), while infants with mild/moderate seizures had scores that were 14.2 points lower (95% CI −26.5 to −1.9 points) when compared to infants without seizures. The adjusted impact of seizures on the WPPSI-R Performance and Verbal IQs was similar to the effect on the FSIQ. The association between seizure severity and adverse cognitive outcome was not modified by the predominant pattern of injury (i.e. basal nuclei vs. watershed) or by the severity of the basal nuclei or watershed injury.
The association between neuromotor outcome and seizures also persisted after adjusting for the severity of injury measured on MRI, with an odds of neuromotor score ≥2 at 20 (95% CI 3 – 140) for children with neonatal seizures when compared to those without seizures.
We performed sensitivity analyses to examine the effect of death and timing of imaging on the results. In order to account for deaths in the data set, we imputed the lowest FSIQ and a neuromotor score of 6 for those children who died prior to neurodevelopmental testing at age four years and found that magnitude of the effect of severe or mild/moderate seizures was similar and the results remained highly significant.
Because imaging changes before the third day of life are best measured using diffusion weighted imaging(18
), but this technique was not available for all infants in this study, we performed sensitivity analysis to restrict the results to the 52 infants who were imaged after this time. Again, we found that effect of severe or mild/moderate seizures was similar, however the P-value was 0.06, reflecting the smaller sample size.