Published online July 3, 2006
PEDIATRICS Vol. 118 No. 1 July 2006, pp. 41-46 (doi:10.1542/10.1542/peds.2005-1524)
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Prediction of Seizures in Asphyxiated Neonates: Correlation With Continuous Video-Electroencephalographic Monitoring

Deidre M. Murray, MDa, C. Anthony Ryan, MDa, Geraldine B. Boylan, PhDa, Anthony P. Fitzgerald, PhDb and Sean Connolly, MDc

a Department of Pediatrics and Child Health, University College Cork, Unified Maternity Services, Cork, Ireland
b Department of Epidemiology, University College, Cork, Ireland
c Department of Clinical Neurophysiology, St Vincent's University Hospital, Dublin, Ireland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. After perinatal asphyxia, predicting which infants will develop significant hypoxic-ischemic encephalopathy and neonatal seizures remains a difficult task. High-risk markers (Apgar score, acidosis, nucleated red blood cells, and resuscitation) have been used to predict neonatal seizures with varying success. The "3 strikes" of Apgar score of <5 at 5 minutes, pH <7.00, and need for intubation have been cited as having a positive predictive value of 80%. We examined whether the predictive values of these markers would be increased if early continuous electroencephalographic monitoring allowed us to accurately identify all neonatal seizures and to grade the encephalopathy.

METHOD. We recruited term infants with perinatal asphyxia. Continuous video electroencephalography was commenced soon after birth and continued for 24 to 72 hours. The abilities of high-risk markers to predict electroencephalographic seizurs, background electroencephalographic activity, and Sarnat grade were examined.

RESULTS. Forty-nine infants were suitable for analysis. Electrographic seizures occurred in 11 of the 49 infants. Encephalopathy was scored by using Sarnat grade (6, severe; 18, moderate; 25, mild) and electroencephalographic findings (4 inactive, 4 major abnormalities, 16 moderate abnormalities, and 25 normal/mildly abnormal). Apgar score of <5 at 5 minutes, pH <7.0, and the need for intubation had positive predictive values for neonatal seizures of 18%, 16%, and 21%, respectively. Combining these markers gave a positive predictive value of 25% and a negative predictive value of 77%. Substituting base deficit or lactate for pH in the 3-strikes model did not improve its predictive value. Apgar score of <5 at 5 minutes, nucleated red blood cells, and a base deficit less than –15 mEq/L showed some association with Sarnat grade. Only 5-minute Apgar score was significantly associated with both Sarnat grade and electroencephalographic grade.

CONCLUSION. After perinatal asphyxia, neither the condition at birth nor the degree of metabolic acidosis reliably predict neonatal seizures.

Key Words: hypoxic-ischemic encephalopathy • video electroencephalography • neonatal seizures • seizure prediction

Abbreviations: PPV—positive predictive value • BD—base deficit • NRBC—nucleated red blood cell • EEG—electroencephalographic • HIE—hypoxic-ischemic encephalopathy • CI—confidence interval

After perinatal asphyxia, the occurrence of seizures remains a significant neurologic event. The outlook for long-term neurologic development is changed dramatically by the occurrence of clinical seizures, which place the infant in the category of moderate-to-severe encephalopathy.1,2 The current markers of fetal distress are poor indicators of neurologic outcome.3,4 Apgar score <5 at 5 minutes, pH <7.0, and the need for intubation in the delivery room all have individual positive predictive values (PPVs) for seizure development of 20% to 30%.5 It has been reported previously, and cited frequently, that these 3 indicators in combination have a much better predictive value, with a PPV of 80%. These factors were termed the "3 strikes" by Perlman and Risser5 in the prediction of neonatal seizures. Base deficit (BD), arterial lactate, and levels of nucleated red blood cells (NRBCs) have also been examined for their ability to predict neurologic outcome with varied results.6–8

All of the previous studies examining the prediction of seizures were based on clinically diagnosed seizures, confirmed by intermittent electroencephalographic (EEG) recordings. However, it is now known that ~60% of neonatal seizures are subclinical and will not be recognized without continuous EEG monitoring.9 We have shown recently that experienced neonatal staff will misdiagnose clinical seizures ~50% of the time.10

Continuous EEG monitoring is the gold standard for accurate neonatal seizure detection. As part of ongoing research into the evolution of EEG in hypoxic-ischemic encephalopathy (HIE), we have been performing early, continuous digital video EEG in infants with this condition. We wished to determine whether the ability of the clinical markers outlined above to predict neonatal seizures would be improved if continuous early video-EEG monitoring allowed all of the seizures to be accurately detected.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
This prospective study was conducted in a large maternity service with an annual delivery rate of 6000. Ethical approval was obtained from our local hospitals ethics committee. From May 2003 to December 2005, infants at high risk of HIE were recruited. Term infants (>37 weeks' gestation) were defined as high risk if they fulfilled ≥2 of the following criteria: (1) initial capillary or arterial pH <7.1, (2) Apgar score <5 at 5 minutes, (3) initial capillary or arterial lactate >7 mmol/L, and (4) abnormal neurology or clinical seizures.

The parents of infants fulfilling the criteria were approached shortly after delivery, and written consent was obtained. Continuous video EEG was recorded from within 3 to 6 hours of birth for 24 to 72 hours. Apgar scores, delivery room resuscitation requirement, initial blood gases, and NRBC levels on day 1 of life were recorded.

Initial blood gases were collected within 30 minutes of delivery. Because pH, BD, and lactate do not differ significantly between capillary and arterial sampling,11,12 these parameters were estimated from capillary blood in cases where no arterial lines were in situ. Each infant was also assigned a Sarnat score based on clinical behavior at 24 hours.13 Digital EEG was recorded continuously from 12 bipolar EEG channels (Taugagreining Nervus monitor). Silver-chloride electrodes were applied to the scalp at F3, F4, C3, C4, T3, T4, P3, P4, O1, O2, and CZ (using international 10–20 system of electrode placement modified for neonates). Continuous digital video imaging of the infant was recorded simultaneously. Physiologic parameters, heart rate, respiration, oxygen saturation, and (where available) direct arterial blood pressure were recorded digitally from the infant's intensive care monitor at the same time and stored with the EEG signal on the digital EEG system. Clinicians were untrained in EEG interpretation and blinded to EEG data. Antiepileptic medications were administered as clinically indicated according to unit protocol.

Video EEG was analyzed visually by an experienced neonatal neurophysiology scientist (G.B.B.) after discharge from the unit. Seizures were defined as repetitive rhythmic activity of >10-seconds duration with a distinct beginning, middle, and end. The background activity of the EEG was graded according to a standardized grading system described previously14 and outlined in Table 1.


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  		TABLE 1 Classification of EEG Background Activity

 
Statistical Analysis
The ability of indicators of fetal distress (pH <7.0, Apgar <5 at 5minutes, intubation in the delivery room, initial lactate, and BD and NRBC level) to predict neonatal seizures was evaluated using positive and negative predictive values. The discriminatory abilities of continuous variables (pH, BD, lactate, NRBCs, and Apgar score) were measured using area under the receiver operator characteristic curves. Mann-Whitney rank sum test and nonparametric trend test were used to test associations between high-risk markers and both Sarnat grade and EEG grade.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Fifty-seven term infants were enrolled in the study. All of the infants were admitted directly to the NICU. Four infants were planned home deliveries, and accurate details of Apgar scores and resuscitation were not available. These 4 infants were excluded from analysis. Of the 53 remaining infants, 49 had continuous early video-EEG monitoring. Only those infants who had continuous EEG monitoring were included in analysis. The majority of infants (42 of 49) were enrolled at birth, and the mean (SD) time from birth to commencement of EEG monitoring was 5.8 (2.7) hours. Seven infants only fulfilled criteria for enrollment after the onset of clinical seizures and their EEG monitoring was commenced >12 hours from birth. The mean (SD) birth weight of the infants was 3346 (658) g, and the gestational age was 40 (1.5) weeks.

Electrographic seizures occurred in 11 (22%) of the 49 infants. All of the infants had clinical signs of HIE graded by Sarnat score: 6 severe, 18 moderate, and 25 in the mild category. Degree of encephalopathy was also graded by EEG findings, as follows: 4 inactive, 4 with major abnormalities, 16 with moderate abnormalities, and 25 normal or with mild abnormalities. The high-risk markers in each of the 49 infants are outlined in Table 2. Apgar scores of ≤5 at 5 minutes occurred in 17 (35%) of 49. An initial pH of ≤7.0 occurred in 19 (39%) of 49. Intubation in the delivery room was required in 29 (59%) of 49 infants. An initial lactate level was available in 45 infants and was >10 mmol/L in 31 (69%) of 45 infants, and BD at –15 mEq/L or more occurred in 20 (41%) of 49. NRBC levels were available in 38 infants and were >10 per 100 white blood cells in 18 (47%) of 38 infants. The time from birth to initial blood gas estimation was <30 minutes in 41 of 49, 30 to 60 minutes in 5 of 49, and unrecorded in 3 of 49 cases.


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  		TABLE 2 High-Risk Markers and Occurrence of Seizures

 
The predictive ability of each of the high-risk markers is shown in Table 3. The individual PPVs of an Apgar score ≤5 at 5 minutes, pH ≤7.0, and the need for intubation in the delivery room were 18%, 16%, and 21%, respectively. We combined 3 markers, denoted the "3 strikes," in seizure prediction to assess their combined predictive value in our patient group.5 Combining these markers did not improve their predictive value. Of the 49 infants, 8 had all 3 of the risk factors, and only 2 of these had seizures, giving a PPV (95% confidence interval [CI]) of 25% (95% CI: 3–65) and a negative predictive value (95% CI) of 78% (95% CI: 62–89). The substitution of BD and lactate for pH in the 3 strikes model did not improve its predictive ability.


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  		TABLE 3 Ability of High-Risk Markers to Predict Neonatal Seizures

 
We also examined the occurrence of high-risk markers in differing encephalopathic grades by using the clinical Sarnat score and the grade of EEG abnormality. Because of the small numbers of infants with severe encephalopathy, those with moderate and severe encephalopathy were considered together. Of the high-risk markers examined, an Apgar score at 5 minutes, a raised NRBC level, and a BD more than –15 mEq/L differed significantly between Sarnat grades (Table 4). Only Apgar score at 5 minutes showed a statistically significant association with EEG grade (P = .026).


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  		TABLE 4 Comparison of High-Risk Markers Between Infants With Mild Encephalopathy and Those With Moderate-to-Severe Encephalopathy

 
Seizures were clinical and electrographical in 9 of 11 cases and electrographic alone in 2 of 11. As already stated, 4 infants fulfilled the criteria for enrollment but did not have continuous EEG monitoring because of technical reasons. In these infants, 2 had clinically suspected seizures and, hence, a clinical Sarnat grade of moderate. The remaining 2 infants had a Sarnat grade of mild.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Supportive care has long been all that clinicians can offer an infant after perinatal asphyxia, allowing them to follow the clinical evolution of the encephalopathy before assigning prognosis. The potential of neuroprotective therapies, such as hypothermia, has raised the importance of accurate prediction of outcome in the first 6 hours of life.15

Our results highlight the difficulty faced by researchers and clinicians in assigning early and accurate prognosis to these infants. Individually, Apgar scores, acid-base disturbance, NRBCs, and the requirement for resuscitation in the delivery room did not reliably predict the occurrence of seizures. Furthermore, we have shown the lack of improvement in prediction using combinations of high-risk markers. This contradicts the frequently cited 3 strikes theory of increasing seizure risk with multiple high-risk markers. Perlman and Risser's5 group who showed a PPV of 80% with a combination of Apgar score, pH ≤7.0, and the need for intubation in the delivery room, was based on a similar population: 96 high-risk infants from a population of ~15000 births. In their group, only 5 infants had clinically diagnosed seizures. It is important to note that in both groups of high-risk infants, there were very small numbers of infants with all 3 strikes. This makes it difficult to draw any conclusions from the predictive values found; however, it is unlikely to be a useful clinical score.

We did find a statistically significant difference in Apgar scores, NBRCs, and BD between infants who developed mild encephalopathy and those who progressed to moderate/severe encephalopathy. The clinical significance of these findings will depend on the individual physician.

Continuous early video-EEG monitoring allowed us to improve our accuracy of seizure detection but did not improve the predictive ability of the early clinical measurements. In addition, we found no improvement in predictive value with the substitution of BD or lactate for pH in the 3 strikes model. The outcome after severe acidosis is variable. This has been shown previously and again in our group.4 Focusing on metabolic acidosis and, in particular, lactic acidosis may identify infants at risk of HIE but will not help in predicting the occurrence of seizures or the grade of the encephalopathy.6,16

We should not be surprised that reactive changes to an underlying pathologic process do not give us the whole picture. Acid-base disturbance is a secondary event caused by inadequate tissue perfusion and oxygenation. Animal studies have shown that the greatest predictor of neuronal damage is hypotension rather than hypoxia.17 In addition, these same animal experiments show that only the fetal lambs that develop suppression of their EEG during periods of induced asphyxia will develop cerebral damage. None of our current "early markers" give us any indication of the degree of hemodynamic or EEG disturbance that the infant has sustained.

Sarnat scoring has a good predictive ability, but it can not be assigned until 24 hours of age, too late for beneficial recruitment to neuroprotective therapies. In contrast, EEG grading can be assigned soon after delivery and offers more reliable prognosis than Sarnat scoring alone.18

EEG remains our best method of predicting neurologic outcome in HIE.19,20 A normal or mildly abnormal EEG in the first 24 hours of life has a PPV of 94% in predicting a normal neurologic outcome. In contrast, a severely abnormal or inactive EEG predicts death or severe disability in 100% of cases. Moderate abnormalities will be associated with neurologic disability in ~60% of cases. Unfortunately, most centers do not currently have access to either the equipment or expertise required for prompt neonatal EEG recording and interpretation.

Early amplitude integrated EEG has been shown to accurately predict the severity of encephalopathy and long-term neurologic outcome.21 For this reason, it has been used in the recruitment of infants with moderate and severe encephalopathy to clinical trials of neuroprotective hypothermia, with promising results.15 However, amplitude integrated EEG shows poor reliability compared with continuous EEG when reported by inexperienced personnel and does not allow localization of pathology or seizure activity.22


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Most infants who develop HIE will have demonstrated some evidence of perinatal distress. However, neither the condition at birth nor the degree of metabolic acidosis reliably predicts the occurrence of seizures. The development of early and expert analysis of neonatal EEG is currently our best hope for advancement in neuroprotective therapies and accurate outcome prediction in HIE.


   ACKNOWLEDGMENTS
 
This study has been supported by grants from the Irish Institute of Clinical Neuroscience and the Health Research Board of Ireland.

We thank the parents of the infants involved in the study and the nursing staff of the Unified Maternity Service, Cork, for their help and enthusiasm.


   FOOTNOTES
 
Accepted Jan 19, 2006.

Address correspondence to C. Anthony Ryan, MD, Unified Maternity Services, Erinville Hospital, Western Road, Cork, Ireland. E-mail: ryant1{at}shb.ie

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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