Antiseizure medications and treatments in neonates

Key points

Initial/emergent management of neonatal seizures includes stabilization of the neonate, assessment and correction of reversible causes of seizures, and evaluation for sepsis/meningitis at the same time as antiseizure medications (ASMs) are initiated.
Despite limited efficacy data and concern for adverse effects, phenobarbital remains the first-line treatment for most neonatal seizures.
Limited evidence supports phenytoin, benzodiazepines, lidocaine, and levetiracetam as second- or third-line agents.
Other third-line agents may also be used for refractory seizures, but there is limited evidence regarding their safety and efficacy.
Empiric pyridoxine, pyridoxal 5′-phosphate (PLP), and folinic acid trials should be considered in neonates with seizures refractory to therapy with multiple ASMs while diagnostic biochemical and genetic testing is performed.

Introduction

Goals of therapy

Untreated neonatal seizures have been shown to cause neuronal apoptosis and are associated with poor neurodevelopmental outcomes in both animal and human studies. Although controversy remains regarding the degree to which seizure treatment might affect outcomes, most providers attempt to control neonatal seizures with the use of antiseizure medications (ASMs). As such, the overarching goal of treatment is usually to minimize the acute seizure burden for the neonate. At the same time, different providers and specific clinical scenarios may warrant a distinct consideration of the potential benefits of seizure treatment against the potential risks. When selecting ASMs, it is helpful to be explicit about the goals of therapy for each individual case.

The majority of neonatal seizures are acute symptomatic seizures. That is, they are symptomatic of acute brain injury such as hypoxic–ischemic encephalopathy (HIE) or stroke. Animal models and observational studies suggest that increased seizure burden in the setting of acute neonatal brain injury is associated with worsened outcomes. For this reason, when treating acute symptomatic seizures, the initial goal of treatment is typically resolution of all seizures. Of note, this includes both clinical seizures and subclinical (electrographic-only) seizures. Over 85% of neonatal seizures are subclinical, with no outward clinical signs visible. Subclinical seizures can only be identified through the use of electroencephalography (EEG). As such, continuous electroencephalography (cEEG) is required for accurate diagnosis of neonatal seizures. The updated neonatal seizure classification from the International League Against Epilepsy (ILAE) emphasizes the key role of EEG in the diagnosis of neonatal seizures and recommends EEG as the first step in the evaluation of a critically ill neonate at risk for or with clinically suspected seizures. If cEEG is not available, amplitude-integrated electroencephalography (aEEG) may be used, although aEEG is known to have lower sensitivity and specificity compared with cEEG. With treatment for neonatal seizures, about half of neonates will have electroclinical dissociation, meaning outward signs might resolve even as EEG seizures continue. cEEG monitoring is therefore particularly important after initiating treatment to accurately evaluate response as treatment is continued and to target complete resolution of seizures.

In contrast, approximately 20% of neonatal seizures are symptomatic of underlying brain malformation or neonatal-onset epilepsy, meaning ongoing seizures are expected. In these cases, the goal of treatment is more likely to reduce the seizure burden as much as possible using oral agents, but with the knowledge that some breakthrough seizures may continue. cEEG may be useful in these cases to clarify which clinical events are true seizures with an electrographic correlate.

In rare cases, such as when palliative care has been selected, the goal of treatment might be only suppression of clinical seizures to maximize patient and parental comfort. In these cases, EEG is not necessary. The main consideration is efficacy of the ASM for the outward control of symptoms.

Regardless, it is essential to establish and communicate the goals of treatment for each neonate with seizures when initiating therapy. Treatment choices are heavily influenced by a shared understanding of the goal of treatment (e.g., complete resolution of seizures, seizure control as best as possible with oral agents, suppression of clinical seizures). These goals may be revisited throughout the course of treatment, and, as goals are revised, good communication is essential.

Overview of therapy

In any case of suspected neonatal seizures, the first steps in management are securing and maintaining the infant’s airway, confirming adequate ventilation, and ensuring adequate circulation and perfusion. cEEG should be placed as soon as possible after the infant is stabilized and can be placed concurrently with subsequent steps in evaluation and treatment. Interventions should not be delayed for EEG placement. The next step in acute management is to assess for reversible causes of seizure, including hypocalcemia, hypoglycemia, and hypomagnesemia. Serum concentrations of electrolytes and glucose should be rapidly obtained and any electrolyte abnormalities or hypoglycemia corrected. Infants should also be evaluated for infectious causes of seizures, such as meningitis and sepsis, with appropriate antimicrobial therapy initiated. If seizures are highly suspected clinically or are confirmed on EEG, a loading dose of an ASM should be given as soon as possible. See Table 13.1 for dosing guidelines and Figure 13.1 for a suggested treatment algorithm.

TABLE 13.1

Antiseizure Medication Dosing and Serum Levels

ASM	Loading Dose	Maintenance Dosing	Target Serum Level
Phenobarbital	20 mg/kg IV; may give additional doses of 10 mg/kg up to 40 mg/kg total	5 mg/kg/day divided into one to two doses	Obtain level 1–2 hr after loading dose; target range 20–40 µg/mL
Phenytoin/fosphenytoin	15–20 mg PE/kg IV; may give additional 10 mg PE/kg once	3–5 mg/kg/day divided into two to four doses	Obtain level 1 hr after loading dose; target level 10–20 µg/mL total or 1–2 µg/mL free phenytoin
Midazolam	0.05 mg/kg IV over 10 min	Continuous infusion of 0.15 mg/kg/hr; may increase stepwise by 0.05 mg/kg/hr up to maximum of 0.5 mg/kg/hr	No established drug-level monitoring
Lorazepam	0.05–0.1 mg/kg IV given over 2–5 min; may repeat up to total dose of 0.15 mg/kg	—	—
Clonazepam	0.01 mg/kg IV	0.01 mg/kg/dose for 3–5 doses	—
Levetiracetam	20–50 mg/kg IV	30–50 mg/kg/day divided into two doses	No established drug-level monitoring
Topiramate	5–10 mg/kg enteral	1–5 mg/kg/day	5–20 µg/mL in adults; not established in neonates

Please see Table 13.2 for lidocaine dosing.

Figure 13.1, General treatment algorithm guided by WHO and ILAE recommendations.

Current ILAE and World Health Organization (WHO) recommendations and expert consensus support phenobarbital as the first-line agent for the treatment of neonatal seizures. Seizures unresponsive or only partially responsive to phenobarbital should be treated with an additional second-line agent: phenytoin, benzodiazepines, or lidocaine. Although not yet included in official guidelines, levetiracetam is increasingly popular as a second-line agent, as well. No clear guidelines exist for third-line treatment, other than use of second-line agents already noted. Choice of a third-line agent is largely dependent on clinician and institutional preference. In neonates with seizures refractory to adequate doses of multiple ASMs and when there is no clear etiology for seizures identified, vitamin-responsive epileptic encephalopathies should be considered. Trials of pyridoxine, pyridoxal 5′-phosphate (PLP), and folinic acid should be performed. Evaluation for specific genetic and metabolic causes of neonatal seizures should also be performed, with consideration of the ketogenic diet in select cases. Neuroimaging should be obtained to evaluate for acute causes of seizure and structural abnormalities as soon as possible; magnetic resonance imaging is the preferred imaging modality. ^, Identification of the underlying cause of seizures can be helpful in guiding the choice of treatment and informing the duration of anticipated treatment.

Antiseizure medications

Phenobarbital

Phenobarbital, although an older ASM, remains the mainstay of treatment for neonatal seizures. The 2011 WHO guidelines on neonatal seizures designate phenobarbital as a first-line treatment. Similarly, surveys of child neurologists and neonatologists confirm that phenobarbital remains the first-choice medication for most physicians treating neonatal seizures. This is largely because phenobarbital has the largest evidence base, with the most animal model data and greatest clinical experience.

Mechanism of action

Phenobarbital is a barbiturate, which acts as an agonist at the gamma-aminobutyric acid type A (GABA-A) receptor to enhance inhibitory neurotransmission. Phenobarbital binding to the GABA-A receptor triggers opening of the postsynaptic chloride ion channel, which in mature neurons results in chloride entering the cell, hyperpolarizing the cell, and thus reducing excitability (see Figure 13.2 A). In immature neurons, however, there is age-specific increased expression of a specific sodium–potassium–chloride cotransporter, NKCC1, that causes immature neurons to have much higher intracellular chloride levels than exist in mature neurons. Due to this high intracellular concentration of chloride in an immature neuron, when the GABA-A receptor is activated to open the chloride ion channel, there is not an influx of chloride. There may be little change, or even an outflow of chloride, with resulting depolarization (excitation). This correlates with the clinical finding that phenobarbital is incompletely effective for controlling neonatal seizures. Ongoing research investigates whether adjunctive agents might enhance the efficacy of phenobarbital by manipulating chloride concentrations (see later discussion of bumetanide). It has also been proposed that phenobarbital reduces excitatory neurotransmission across the glutamatergic synapse through action on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainite glutamate receptor (see Figure 13.2 B).

Efficacy

Despite extensive clinical use, there is a paucity of high-grade clinical evidence supporting the efficacy of phenobarbital. The first published randomized trial of phenobarbital for the treatment of neonatal seizures was conducted by Painter and colleagues in 1999. This study included 59 neonates with acute seizures confirmed on EEG. The majority had identified acute causes of seizure, such as HIE or stroke. Subjects were randomized to receive either phenobarbital first or phenytoin first. If seizures continued, the other drug was added. Among neonates receiving phenobarbital first, only 43% had control of seizures (vs. 45% response rate with phenytoin). With the addition of phenytoin, this increased to 57%. Subsequent retrospective and small prospective studies have similarly reported that phenobarbital monotherapy provides seizure control rates of 43% to 63%. Consistent across these studies has been lower efficacy in neonates with significantly abnormal background EEG ^, or with worse initial seizure burden. A second randomized trial was published in 2020 comparing levetiracetam to phenobarbital for neonatal seizure treatment. Eighty-three neonates with seizures were randomized and received either levetiracetam 40 mg/kg or phenobarbital 20 mg/kg as first-line therapy, with an additional 20 mg/kg of levetiracetam or 20 mg/kg of phenobarbital if seizures continued. The other medication was given as second-line therapy if seizures were not controlled. After the first dose, seizures stopped in 70% of those treated with phenobarbital versus 21% in the levetiracetam group. This increased to 80% for phenobarbital and 28% for levetiracetam after the second dose. The efficacy of phenobarbital as the second-line medication was 54%, and the efficacy of levetiracetam was 17%. Phenobarbital (20–40 mg/kg) was significantly more efficacious than levetiracetam (40–60 mg/kg) in this study.

Of note, evidence suggests that phenobarbital should only be used for treatment of existing seizures and not for prophylaxis before seizures in neonates with encephalopathy. A Cochrane Review found that, although prophylactic phenobarbital did reduce the risk of seizures for neonates with perinatal asphyxia, there was no reduction in mortality and no data to suggest improved long-term outcomes. Similarly, prophylactic phenobarbital does not enhance the efficacy of hypothermia in limiting brain injury from HIE.

Dosing

Initial phenobarbital treatment for confirmed seizures is a loading dose of 20 mg/kg intravenous (IV). After the initial load, neonates are typically started on short-term maintenance therapy of 5 mg/kg/day, divided into either twice-daily doses or as one daily dose. ^, ^, ^, The recommended loading dose is the same in the setting of therapeutic hypothermia. If seizures do not subside on EEG after the initial 20-mg/kg loading dose, additional doses of 10 mg/kg can be given up to a total load of 40 mg/kg. ^, A phenobarbital level should be checked 1 to 2 hours after the loading dose is given, with a target level of 20 to 40 µg/mL. ^, ^, Some patients may require levels up to 60 µg/mL to achieve seizure control, although increased sedation is noted with levels >50 µg/mL.

The half-life of phenobarbital varies widely with postnatal age, especially when given orally. In the first 10 days of life, there is delayed and incomplete absorption of phenobarbital from the gastrointestinal tract and the half-life is typically long, with increasing clearance in days 11 to 30 and 31 to 70. ^, Therefore, neonates may require increasing doses to achieve the same therapeutic effect after the first few weeks of life.

Metabolism of phenobarbital is inhibited by several drugs, including phenytoin. These medications may increase serum phenobarbital concentrations. There are conflicting reports in the current literature regarding the effect of hypothermia on phenobarbital clearance. Shellhaas et al. found that therapeutic hypothermia did not influence clearance of phenobarbital in a study of 39 infants with seizures undergoing cooling for hypoxic ischemic encephalopathy. A small single-center study of 19 neonates, however, found that hypothermic infants had higher plasma concentrations and longer half-lives of phenobarbital compared with their normothermic counterparts.

Adverse effects, contraindications, and monitoring

The most commonly encountered side effects with phenobarbital use are sedation and respiratory depression. ^, ^, Other potential adverse effects include hypotension, skin rash, hepatotoxicity, and blood dyscrasia. A large retrospective study showed an association between increased neonatal exposure to phenobarbital and worse neurodevelopmental outcomes. This included cognitive and motor scores on the Bayley Scales of Infant and Toddler Development (8- and 9-point decrease per 100 mg/kg cumulative dose) and increased rates of cerebral palsy (2.3-fold increase per 100 mg/kg phenobarbital). This is in keeping with the body of animal evidence demonstrating increased neuronal apoptosis, altered synaptic development, and long-term behavioral changes with early phenobarbital use. ^, ^, Thus, although phenobarbital remains commonly used, there are concerns regarding overuse and adverse neurodevelopmental effects and an urgent need for alternative drugs.

Phenytoin/fosphenytoin

Phenytoin/fosphenytoin is a common second-line agent for the treatment of neonatal seizures. ^, A recent systematic review demonstrated that there is no strong evidence that phenytoin is superior or inferior to the alternative second-line ASMs levetiracetam or lidocaine. WHO guidelines on the treatment of neonatal seizures also recommend phenytoin as a second-line treatment after phenobarbital, along with consideration of a benzodiazepine or lidocaine. A 2009 survey of European neonatologists found that phenytoin was most commonly used as a third-line treatment after benzodiazepines.

Mechanism of action

Phenytoin primarily acts at the glutamatergic synapse by inhibiting voltage-gated sodium channels (see Figure 13.2 B). In doing so, phenytoin prevents depolarization of the presynaptic neuron, which in turn inhibits excitatory neurotransmission at the glutamatergic synapse. Fosphenytoin is a phosphate ester prodrug of phenytoin that can be given parenterally and is associated with fewer infusion-related adverse effects, but it is more expensive.

Efficacy

In the only randomized controlled trial of phenytoin versus phenobarbital for first-line treatment of neonatal seizures, phenytoin had a response rate of 45% with complete seizure cessation, similar to phenobarbital. In a later study, among neonates with seizures refractory to phenobarbital, phenytoin achieved seizure control in 16%. There have been specific reports of the efficacy of phenytoin in treating neonatal-onset encephalopathies, including SCN2A and KCNQ2 encephalopathy. ^, Further work is needed to clarify whether phenytoin has superior efficacy compared with other agents for these diseases.

Dosing

The typical loading dose of phenytoin is 15 to 20 mg/kg IV. ^, Of note, fosphenytoin is typically dosed in phenytoin equivalents (PEs); thus, a dose of 20 mg/kg phenytoin is equivalent to fosphenytoin 20 mg PE/kg. Neonates receiving phenytoin must have cardiac monitoring during infusion therapy per current WHO guidelines, and the infusion rates should not exceed 1 to 3 mg/kg/min for phenytoin or 2 mg/kg/min for fosphenytoin, given the risk for arrhythmia and/or bradycardia, especially with rapid infusions of phenytoin. An additional 10-mg/kg load may be considered if seizures persist. Further repeat doses are to be avoided due to the risks of toxicity with higher serum levels. Phenytoin levels should be obtained 1 hour after the loading dose is given, with the goal range being 10 to 20 µg/mL. Increasing adverse effects are seen at concentrations >30 µg/mL. Because phenytoin is albumin bound, in patients with abnormal albumin levels a free phenytoin level may be more reliable. A therapeutic range for free phenytoin is typically 1 to 2 µg/mL.

Maintenance dosing is typically 3 to 5 mg/kg/day divided two to four times daily. ^, However, because of rapid hepatic metabolism in the neonate, it can be challenging to maintain therapeutic phenytoin levels even with four-times-daily dosing. Thus, dosing is frequently adjusted to target a blood level in the goal range and is rarely continued beyond the acute period.

Adverse effects, contraindications, and monitoring

There are several drug–drug interactions to consider when using phenytoin. Acutely, the most important is avoidance of phenytoin when lidocaine has recently been given, as these drugs have a similar mechanism of action and combined have a much increased risk for cardiovascular effects. When considering chronic use, aluminum-, magnesium-, or calcium-containing antacids reduce the absorption of phenytoin, and valproic acid displaces phenytoin from albumin-binding sites and inhibits its metabolism. Phenobarbital and carbamazepine may also have variable effects on the serum concentration of phenytoin.

Several adverse effects have been seen with phenytoin use in neonates and older children. In the trial by Painter and colleagues, there were no significant adverse effects, and no changes in heart rate, heart rhythm, or respiratory status were observed. However, phenytoin has been described as causing arrhythmias, hypotension, and hepatotoxicity. ^, ^, Soft-tissue injury from extravasation of phenytoin has also been described, with the development of blue discoloration and blistering noted. ^, ^, All of these effects are less severe with fosphenytoin versus phenytoin. ^, ^, One case report in a 1-month-old infant described ileus at toxic phenytoin levels (serum concentration 91.8 µg/mL).

The long-term risks of phenytoin administration are less clear. Similar to effects seen with phenobarbital, phenytoin has been demonstrated to cause neuronal apoptosis in the developing white matter of rat pups. Widespread dose-dependent neurodegeneration has been demonstrated in rat pups, with a threshold dose of 20 mg/kg. Specific effects on the cerebellum have also been studied, with cerebellar cells and motor coordination deficits seen in rat pups exposed to phenytoin. Further study is needed to determine whether these animal studies translate to clinical deficits in humans.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here