Seizure Burden in Neonatal HIE: (1) Importance of Detection and Management, and (2) Implications for Subsequent Brain Development

November 2024

Introduction

Seizures are a frequent and important feature of hypoxic-ischemic encephalopathy (HIE) (see, for reviews,^1,2). Approximately 50% (30-65%) of term infants with moderate to severe HIE exhibit electrographic seizures, and the latter begin principally in the first 12-24 hours after birth.¹ Multiple reports have shown that the seizure burden (SB), usually expressed as total SB (total duration in minutes for all electrographic seizures) and in some studies also as maximum hourly SB (highest electrographic seizure duration in a 1-hour period), is associated with  neurological outcome, with higher SB associated with poorer outcome (see later). A considerable clinical and experimental literature suggests that seizures are harmful to developing brain (see later). Thus, attempts to diminish SB by treatment with anti-seizure medication (ASM) have seemed reasonable. Two recent reports present data that suggest opposite conclusions on this important issue.^3,4

In the following, I will discuss briefly the two reports just noted, the issues of detection and management of SB, and the potential effects of SB on the developing infant brain. I will suggest a path forward in our assessment and management of the term newborn with HIE and seizures.

Seizure Burden—Detection, Management and Outcome

Detection, management and outcome of SB, most often in newborns with HIE, have been the focus of multiple excellent studies over the past two decades.^3-9 Concerning detection, both the American Clinical Neurophysiology Society and the International League Against Epilepsy have considered continuous, conventional (multichannel) EEG (cEEG) monitoring as the gold standard for most accurate identification of neonatal seizures and the best guide for treatment.^1,10-12 This recommendation is buttressed by the widely accepted observations that non-epileptic paroxysmal clinical phenomena are often mistaken for seizures and that electrographic seizures often exhibit no clear clinical correlates.¹ Concerning management, phenobarbital is recommended as the first-line anti-seizure medication (ASM) by the WHO and the Newborn Brain Society.¹ Concerning outcome, higher SB has been generally considered to be associated with poorer subsequent neurodevelopmental function (see later).

On this background, Hunt and coworkers³ reported on a multicenter (13 sites in 3 countries), randomized clinical trial of newborns (>35 weeks’ gestation) with moderate to severe encephalopathy to determine if drug treatment of all clinically and electrographically detected seizures (ESG group), compared with the treatment of clinically detected seizures alone (CSG group), reduced mortality and neurodevelopmental morbidity through a potential reduction in SB. Electrographic seizures were detected by amplitude integrated EEG (aEEG), not cEEG. Notably, there was no difference in mortality or neurodevelopmental disability nor in SB between the two groups. Moreover, cognitive outcome appeared to be worse in the ESG group. The authors concluded that “despite our increasing reliance on bedside aEEG as a neuromonitoring tool, the issue of whether or not seizure detection should trigger administration of conventional, potentially neurotoxic anticonvulsant drugs remains unresolved.”³

The report of Hunt et al.³ provoked two excellent commentaries.^13,14 Among the criticisms of the study and its conclusions were lack of power (related in part to the loss of equipoise generated during the study by the results of the report of Srinivasakumar et al.⁴) (see later), the lack of monitoring with cEEG, the recommended method for quantitating SB, the minimal difference in cognitive scores between the ESG and CSG groups, and the inclusion of all seizure etiologies (25-30% of cases did not have HIE as cause of seizures).

Different conclusions concerning detection, management and outcome of SB were drawn in the report of Srinivasakumar et al.,⁴ published during the course of the trial of Hunt et al. The former study was a single center, prospective, randomized control trial in term infants with moderate to severe HIE (n=69). All infants were monitored by cEEG. Infants were assigned randomly to either treatment of electrographic seizures alone (ESG) or treatment of clinical seizures alone (CSG). When compared to the CSG, treatment of EEG seizures in the ESG resulted in a shorter time to treatment from seizure onset, a significant decrease in electrographic SB, and a decrease in the number of seizures. MRI injury scores (at 7-10 days of age) were lower in the ESG than in the CSG. Upon neurodevelopmental evaluation at 18 to 24 months, increasing neonatal SB in the combined cohort was significantly associated with lower performance scores across all domains of BSID-III. However, the study was not powered to delineate an impact on overall neurodevelopmental outcome between the two groups. The authors concluded that “cEEG monitoring and treatment of electrographic seizures results in a significant reduction in SB. Increasing SB is associated with more severe brain injury and significantly lower performance scores on BSID-III.”⁴

Although, in my view, the report of Srinivasakumar et al.⁴ supports the value of cEEG monitoring of electrographic seizures, the quantitation of SB, and the attempts to reduce this burden by treatment with ASM, the question remains whether the reduction of SB afforded by early detection by cEEG monitoring and ASM treatment results in improved neurodevelopmental outcome. As noted by both Hunt et al.³ and Srinivasakumar et al.,⁴ to answer that question would require a much larger clinical trial. In the current absence of such a trial, it is useful to consider (1) whether neonatal seizures are deleterious to developing brain and (2) whether the means to minimize such seizures by currently used ASMs are also deleterious.

Deleterious Effects of Neonatal Seizures on Developing Brain

The deleterious effects of neonatal seizures on developing brain are divided best into those related to single prolonged seizures and those related to briefer recurrent seizures (see, for review, ^1,15). I will emphasize the latter because they predominate in the newborn.

Single Prolonged Seizures

 Single prolonged seizures are relatively uncommon in newborns; brain injury in this context usually is related to apnea, hypoventilation, hypoxia, cardiovascular collapse, increased cerebral energy consumption, cerebral energy failure and neuronal death. The decline in high energy phosphates in brain with neonatal seizures and their recovery after phenobarbital treatment have been documented in the living infant by phosphorus magnetic resonance spectroscopy (MRS).^1,16 A number of pre-clinical studies have shown a relation between prolonged seizures and exacerbation of hypoxic-ischemic neuronal injury.^1,17,18 In one study with careful neuropathological data, the increased injury occurred exclusively in the hippocampus.¹⁷ This finding is particularly notable because hippocampal neuronal injury is characteristic of infants with HIE (see later).

Multiple Recurrent Seizures—Pre-clinical Studies

Multiple recurrent seizures are most characteristic of the infant with HIE. Of particular relevance in this context is evidence from excellent experimental models utilizing developing animals and showing the deleterious consequences of recurrent seizures, not necessarily prolonged, involving long-term functional, morphological and physiological deficits.^1,19-23 The most consistent functional disturbances involve deficits in cognition, visual-spatial memory and learning, consistent with the locus of the principal structural deficits in the hippocampus (see later). The morphological correlates of the functional disturbances involve neuronal developmental abnormalities rather than neuronal loss. The most severe disturbances occur in the hippocampus and include (1) dendritic spine loss in CA3 pyramidal cells and (2) a distinctive pattern of synaptic reorganization of axons and terminals of the dentate granule cells (i.e., mossy fibers).²¹ The degree of this “sprouting” of mossy fibers correlates with the severity of the cognitive deficits in the animal models. Moreover, (3) dentate granule cell neurogenesis, which, unlike other cortical areas, persists in the human neonatal period,²⁴ is impaired after recurrent seizures in the animal models.²⁵ It seems highly plausible that the hippocampus and its connections are crucial sources for the subsequent cognitive deficits observed in human infants, as described earlier and discussed further later. Concerning physiological consequences, recurrent seizures also lead to glutamate receptor molecular alterations that favor subsequent neuronal excitability and, therefore, epileptogenesis.¹ The latter is a recognized sequela of neonatal HIE.^1,2

Multiple Recurrent Seizures—Clinical Studies

Although few data are available concerning specific structural deficits related to recurrent seizures in infants with HIE, one large study utilizing structural MRI and proton MRS showed that seizure severity (frequency and duration) was associated with enhanced abnormalities in “basal nuclei” and “cerebral border zones.”²⁶ Whether this finding was indicative of seizures enhancing cerebral injury or of more severe cerebral injury causing more seizures is unclear, although the investigators interpreted multivariable linear regression models to favor the former conclusion.²⁶

As noted earlier, excellent experimental studies suggest that recurrent neonatal seizures lead to later developmental impairments in hippocampal/limbic neuronal structures. However, I am unaware of any specific data in human infants concerning effects of recurrent neonatal seizures on subsequent development of hippocampus and its limbic (e.g., mammillary bodies) and diencephalic (e.g., thalamus) connections. Because hippocampal neurons are especially vulnerable to neonatal hypoxic-ischemic injury/necrosis,^24,27,28 it is difficult to distinguish initial destructive effects and their sequelae from later developmental effects, although both phenomena may co-exist. This difficulty is illustrated by several excellent studies of children (5- and 10-year-olds) after neonatal HIE that show, by MRI, diminished volumes of hippocampi and/or mammillary bodies, the latter a key part of hippocampal circuitry.^29-31 The deficits correlated with evidence of hippocampal dysfunction, including deficits in memory processing speed and overall cognition (patient numbers were too small to address a specific effect of recurrent seizures). That these later morphological and functional limbic deficits may represent, in part, sequelae of the acute hypoxic-ischemic injury is suggested by recent work with MRI (utilizing especially thin slices) showing that mammillary body lesions are apparent in the first week of neonatal HIE in as many as 40% of cases.^32,33 A relation between recurrent neonatal seizure activity and these acute lesions or the subsequent limbic abnormalities in childhood was not addressed. Thus, at present, a clear relation between recurrent neonatal seizures or other manifestations of increased SB and impaired hippocampal/limbic development, comparable to the relation shown in experimental studies (see earlier), has not yet been proven in human infants with HIE. On balance, however, as noted later, I favor the notion that recurrent neonatal seizures as quantitated as SB do have a deleterious effect on subsequent brain development in human infants.

Are ASMs Deleterious to Developing Brain?

Because it is beyond the scope of this presentation to discuss all ASMs, I will focus on phenobarbital, the most commonly used, first-line ASM for neonatal seizures worldwide. The WHO and the Newborn Brain Society recommend phenobarbital as the first-line therapy for neonatal seizures.¹ In mature neurons the drug activates GABA_A receptors, allowing Cl^– influx and thereby inhibition. However, in neonatal brain many neurons have high intracellular Cl^–levels, and opening the GABA channel in such neurons can cause Cl^– efflux and excitation instead of inhibition (see later). Nonetheless, on balance the drug is generally an effective anticonvulsant.

Concern has been raised, principally from experimental studies in a rat model,^34,35 about potential toxicity of phenobarbital. Apoptotic neurodegeneration was observed within 24 hours of administration of phenobarbital, as well as several other anticonvulsants. (Notably, levetiracetam did not produce these effects.³⁶) The neuronal death was associated with reduced expression of neurotrophins and survival-promoting proteins in brain. The relevance to human infants remains unclear.

Currently, the beneficial anticonvulsant effect of phenobarbital has outweighed concerns for neurotoxicity. Nevertheless, search for agents without the possibility of GABA-mediated excitation has been stimulated. Bumetanide and levetiracetam, among others, have been studied.^37,38 Bumetanide acts by inhibiting the Cl^– cotransporter (NKCC1) that results in immature neurons in the elevated Cl^– levels referred to earlier. Thus, in the presence of bumetanide, activation of GABA_A receptors by phenobarbital restores the latter’s inhibitory effect. Levetiracetam acts by preventing neurotransmitter release by binding to a presynaptic vesicle protein, SV2a.¹ Although beyond the scope of this Commentary, both bumetanide (as add-on therapy with phenobarbital)³⁷ and levetiracetam¹ have shown potential benefit. Concerns about ototoxicity have dampened enthusiasm for bumetanide. Levetiracetam currently is under renewed investigation in a clinical trial in Europe. (See Anwar T et al.³⁹ for a recent review of current ASMs.)

Seizure Burden—Cause or Consequence of Brain Injury/Dysmaturation?

Although the findings in pre-clinical models suggest that both enhanced neuronal injury and dysmaturation can result from neonatal seizures, it has been considerably more difficult in human studies to establish causal relationships (see earlier concerning injury and dysmaturation in limbic structures). Considerable work has shown in the setting of HIE that severity of SB is associated with overall severity of MRI evidence of brain injury in the neonatal period, as well as with degree of impairment of neurodevelopmental outcome.^{1,4,5,38,40-42} The key question has been whether these relations reflect a simple association, i.e., severe seizures are a manifestation of severe neonatal pathology, or whether pronounced recurrent seizures exacerbate the hypoxic-ischemic injury and lead to worse neurodevelopmental outcome. Earlier studies have suggested that such exacerbation does occur.²⁶ Moreover, in two large, careful studies, multivariate analysis indicated that severe neonatal SB is independently associated with impaired neurodevelopmental outcome, even after adjusting for severity of MRI evidence of brain injury (and exposure to ASM).^4,5 However, the MRI measures of severity of brain injury are relatively crude from the regional and cellular perspectives. In particular, as described earlier, the best experimental data point to recurrent seizures causing disturbance of hippocampal/limbic cellular development, and, to my knowledge, no information is available in human infants to assess later hippocampal structural development and connectivity in relation to SB. Although I favor the notion that both destructive lesions and subsequent developmental disturbances of limbic structures (hippocampus, mammillary bodies, thalamus) occur in the context of HIE and recurrent seizures, this idea has not been proven conclusively in human infants. Careful studies of neonatal SB via quantitative seizure detection and of subsequent development of limbic and related brain structures via advanced MRI methods are needed.

Conclusions

To answer conclusively the critical questions in HIE concerning the relations between SB, management and effects on structural and functional outcomes, all that is needed is a very large, multicenter, double-blinded, randomized clinical trial. Advanced MRI methods should be directed not only at major vulnerable regional structures, e.g., cerebral cortex, thalamus, but especially hippocampal structures and connectivity both in the neonatal period and subsequently. I use the term “all that is needed” as an intentional understatement because such a study would be extremely difficult to carry out, not only because of logistical and methodological challenges, but also because of ethical concerns. Srinivasakumar et al.⁴ suggest “a meta-analysis with other centers that have similar data” or “a collaborative with institutions with similar clinical practices and follow-up.” A similar conclusion has been drawn by Alharbi et al.⁵ after their large study.

Recommendations

I propose the following recommendations concerning management of the newborn with HIE.

• Firstly, detection and treatment of seizure activity in the infant with HIE as early as possible after birth. Recognizing the logistical challenges in the referring, often nonacademic birth center, nonetheless we should recall the work of Gunn and collaborators showing that subsequent cerebral hypothermia is not neuroprotective when begun after the onset of seizures in the well-characterized fetal sheep model.⁴³
• Secondly, upon arrival at a cooling center, prompt detection and quantitation of SB by cEEG.
• Thirdly, prompt treatment for seizures, initially with phenobarbital. However, anticonvulsive agents without GABA_A agonist activity or with ability to correct high intracellular Cl^– levels in neurons should be sought. (Perhaps levetiracetam or bumetanide can serve as examples for future drug development. See Anwar et al.³⁹ for more specific details.)
• Fourthly, careful assessment by advanced MRI techniques (in both the neonatal period and subsequently) to assess not only cerebral cortical and diencephalic (thalamus) structure but especially hippocampal/limbic structures and their development in relation both to SB and to ASM management.
• Fifthly, careful follow-up of cognitive development, with a greater emphasis on limbic functions, e.g., memory functions, visual-spatial abilities, learning, emotional regulation, etc.

These recommendations are made with the awareness that some represent very difficult challenges. Nonetheless, in my view, improving outcome for the many infants with HIE and seizure phenomena is one of the leading challenges in current neonatal neurology.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

References

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