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Summary: Purpose: Neonatal seizures are relatively common and an important early sign of acute encephalopathy in those who survive infant heart surgery. The contemporary occurrence of seizures in this setting is not fully known, and their electrographic characteristics are incompletely described. This study describes the characteristics of electrographic neonatal seizures (ENSs) in contemporary infants with congenital heart disease (CHD) surgically repaired by using cardiopulmonary bypass, with or without deep hypothermic circulatory arrest.
Methods: Consecutive infants undergoing heart surgery were monitored by video-EEG for 48 h postoperatively to establish the time of first seizure, total number of ENSs, site(s) of ENS(s) origin and other characteristics.
Results: ENSs occurred in 21 (11.5%) of 183 infants. None had clinically visible seizures. The mean time to the first ENS was 21 h (range, 10–36 h). The total number of ENSs among the entire cohort was 1,429. Mean total number of ENSs per patient over a 48-h period was 72 (range, 1–217). Phenobarbital administration was associated with a ≥50% reduction in seizure counts in five (41.7%) of 12 subjects.
Conclusions: ENSs were relatively common in a large, contemporary cohort of infants after infant heart surgery. A wide variation was noted in seizure burden, but many experienced numerous seizures. Electrographic neonatal seizures are a candidate outcome end point in future neuroprotection trials in this patient population.
Seizures are a common and ominous sign in the newborn infant and are associated with a substantial risk of morbidity and mortality (1–5). A growing concern exists that seizures per se may actively contribute to some part of the infant's ultimate unfavorable outcome (6–8). Infants who undergo heart surgery have an especially high risk of seizures. In the earliest era of congenital heart defect (CHD) surgery, postoperative seizures were reported in ≤50% of patients (9,10). In the time period examined by the Boston circulatory arrest trial (1988–1992), clinical seizures were reported in 11 (6.4%) of 170, and electrographic seizures, in 27 (19.8%) of 136 infants who underwent surgical repair of transposition of the great arteries (TGA) by using a randomly assigned intraoperative support strategy of either cardiopulmonary bypass (CPB) or deep hypothermic circulatory arrest (DHCA) (11). A more recent Boston study between 1992 and 1996 evaluated two types of blood gas–management strategies during CPB and documented EEG seizures in six (5%) of 116 neonates and infants undergoing repair of a variety of cardiac defects, except for “single ventricle” lesions (12). In a study from this institution (1992–1997), infants who survived infant heart surgery using DHCA for a wide variety of CHDs displayed clinical seizures in 17.7% of the whole group (13). However, subgroups were noted with particularly high percentages of seizures depending on their specific CHD anatomy, the duration of DHCA, and the presence of comorbid genetic conditions.
The visual diagnosis of seizures in the newborn is fraught with errors of overdiagnosis and underdiagnosis. The use of neuromuscular blockade, for example, renders clinical recognition of neonatal seizures nearly impossible. Consequently, it is appreciated that the EEG is the gold standard for the detection and quantification of electrographic neonatal seizures (ENSs) (14). This study was conducted to measure the contemporary occurrence of postoperative ENSs for infants with a wide variety of CHDs who undergo infant heart surgery by using CPB with or without DHCA. The specific characteristics of the ENSs, associations with magnetic resonance imaging (MRI) findings, and response to antiepileptic drug (AED) treatment are emphasized in this report.
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Neonatal seizures remain a classic sign of high risk for neonates, a situation that has not changed during the past 30 years (1–3,5,17–20). Specifically, the occurrence of neonatal seizures after infant heart surgery has long been recognized (9,13), but the incidence of clinical seizures appears to be waning. Postoperative seizures correlate with poorer neurodevelopmental scores on subsequent short-term testing (21), but their long-term significance is less clear (22,23).
Because of the uncertainties associated with clinical neonatal seizure detection and quantification, the use of continuous video-EEG monitoring provides a more accurate method to detect and quantify ENSs in this vulnerable patient population (14). Although this study was not intended to measure the occurrence of clinical seizures, it is noteworthy that bedside caretakers detected no clinical seizures. It is well known that ENSs may sometimes be associated with paroxysmal fluctuations in vital signs such as sudden periods of tachycardia or blood pressure instability, especially in those with neuromuscular blockade (24–26). Indeed, in this post–cardiac surgery population, caregivers occasionally activated the “event” button for a concern of seizures with pure autonomic signs. However, not one of these indexed events was accompanied by an electrographic seizure in this study population. Still, electrographic seizures have occasionally been discovered in the past during routine patient care when fluctuations of vital signs have led to an EEG examination. Because of the difficulties with the clinical recognition of seizures, video-EEG monitoring is the ideal method to detect the presence and number of seizures. The availability of relatively inexpensive equipment and the efficient review of long periods of EEG records can now be accomplished in an acceptably brief period.
In the contemporary practice of infant heart surgery, postoperative ENSs are relatively common, occurring in 11.5% of 183 monitored infants. Their “burden” of seizures varied widely, with total seizure counts ranging from one to 217, but most patients had numerous seizures. Prior reports of electrographic seizures after newborn heart surgery were provided by Newburger (11) and du Plessis (12). The details of the electrographic seizure characteristics in the original Boston circulatory arrest trial were described by Helmers et al. (27), who described multiple seizures, mostly clinically silent, with first onset between 4 and 36 h after surgery. Although the total seizure counts per patient were not specified, the combined duration of electrographic seizures per patient ranged from 6 s to 980 min.
A glimpse of the “natural history” of neonatal seizures can be appreciated in this study because AED treatment was not possible for hours after subclinical onset of ENSs. Clearly, some appeared to enjoy spontaneous cessation of ENSs without any AED administration. For many, the first dose of PB had little impact on hourly seizure counts. However, these results must be interpreted cautiously because a wide range of initial drug dosing occurred. Nevertheless, 15 (71%) of 21 required video-EEG monitoring beyond the end of the 48-h study period because seizures persisted despite multiple AEDs. A true efficacy study of AEDs in the treatment of neonatal seizures has never been performed. Several small series reported a variable percentage of seizure reduction after PB administration, but none was placebo controlled (28–33). This is a major limitation because, as this study demonstrates, some infants have an apparently spontaneous remission of seizures before drug administration. Painter's study (34) compared PB with phenytoin (PHT), but, lacking a placebo-control arm, absolute efficacy could not be measured.
Reasonable anatomic correlations between the location(s) of acute injury on MRI and site(s) of onset of ENSs were found. The high occurrence of imaging abnormalities suggests that MRI examinations should be considered in the evaluation of those in whom postoperative seizures developed.
It is generally assumed that the major force behind the mortality and morbidity of neonatal seizures is the underlying etiology that triggered them in the first place, such as hypoxic ischemic encephalopathy, meningitis, or trauma. However, growing evidence in animal models suggests that seizures per se may leave a lasting mark on the immature central nervous system (35–37). In Holmes's study (6), a series of 25 brief seizures induced by fluorothyl led to subsequent measurable impairments in visual spatial memory and increased seizure susceptibility. Indeed, even the profile of postnatal expression of γ-aminobutyric acid (GABA)A receptor subunits is altered in animals after neonatal seizures (7,8).
Newborns with CHD who face infant heart surgery by using CPB with or without DHCA face an exaggerated risk for both postoperative seizures and neurodevelopmental abnormalities and constitute an ideal population for future neuroprotection trials (38). More generally, neonatal seizures are a good target end point for other neonatal neuroprotection trials, including hypothermia trials for neonatal hypoxic ischemic encephalopathy (39). Future neuroprotection studies in the infant heart surgery population could consider the prevention of onset of electrographic neonatal seizures, detected by continuous video-EEG monitoring. Furthermore, those in whom subclinical ENSs develop may be an appropriate group with which to explore definitive, placebo-controlled efficacy trials of PB, BZDs, or other AEDs.