Treatment of neonatal seizures

INTRODUCTION — Management of neonatal seizures involves accurate diagnosis of seizures, expedited evaluation and targeted treatment for their etiology, and medication to abolish the electrographic seizures. This topic will discuss the approach to treatment of neonatal seizures.

The etiology, clinical features, and diagnosis of neonatal seizures are discussed separately. (See "Etiology and prognosis of neonatal seizures" and "Overview of neonatal epilepsy syndromes" and "Clinical features, evaluation, and diagnosis of neonatal seizures".)

EXPEDITED TREATMENT — The occurrence of neonatal seizures may be the first, and perhaps the only, clinical sign of a central nervous system disorder in the newborn infant. Seizures may indicate the presence of a potentially treatable etiology and should prompt an immediate evaluation to determine cause and to institute etiology-specific therapy. In addition, seizures themselves may require urgent therapy, since they can adversely affect the infant's homeostasis and contribute to further brain injury. Some types of neonatal seizures are associated with a relatively high incidence of early death and, in survivors, a high incidence of neurologic impairment, developmental delay, and postneonatal epilepsy. Treatment that lowers the seizure burden may be associated with improved outcomes [1].

Importance of treatment pathway — As recommended by the International League Against Epilepsy (ILAE), all neonatal units should use a local or national pathway or algorithm for the treatment of neonatal seizures to expedite evaluation and treatment [1].

Neurology consultation — Pediatric neurology should be consulted as soon as neonatal seizures are suspected, both to initiate electroencephalography (EEG) monitoring and to advise on evaluation and management.

In resource-limited regions without access to urgent neurology consultation, evaluation and management of suspected neonatal seizures is challenging; diagnostic certainty is compromised without EEG guidance. Nevertheless, etiologic treatment may be effective for neonates with provoked seizures (eg, due to hypoglycemia), and evidence-based treatment (eg, initial loading dose of phenobarbital) should be started even if there is no available pediatric neurology consultant.

Whenever possible, discussion with a pediatric neurologist and consideration of transfer to a secondary or tertiary center is advised for neonates with frequent seizures, status epilepticus, or neonatal-onset epilepsy syndromes.

ETIOLOGIC THERAPY — Treatment directed at the cause of neonatal seizures is critical since it may prevent further brain injury. This is particularly true for seizures associated with some metabolic disturbances (eg, hypoglycemia, hypocalcemia, and hypomagnesemia) and with central nervous system (CNS) or systemic infections. Furthermore, some neonatal seizures may not be effectively controlled with antiseizure medications (ASMs) unless their underlying cause is treated.

The most common etiologies of neonatal seizures are reviewed in the table (table 1).

Neonatal encephalopathy — Neonatal encephalopathy (and associated hypoxic-ischemic encephalopathy [HIE]) is the most common cause of neonatal seizures [2]. Even with therapeutic hypothermia for neuroprotection, approximately 50 percent of newborns with HIE have electrographic seizures [3].

The treatment of neonatal encephalopathy is discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

CNS infection — Neonates with seizures should be presumed to have an infectious etiology until proven otherwise. Thus, a sepsis evaluation is mandatory. Infection of the CNS is a relatively common cause of neonatal seizures and should be treated with broad-spectrum antibiotics at doses sufficient to treat meningoencephalitis.

Treatment of infection and meningitis in neonates is discussed separately. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "Bacterial meningitis in the neonate: Treatment and outcome" and "Group B streptococcal infection in neonates and young infants", section on 'Management'.)

Metabolic disturbances — Metabolic disturbances are a treatable common cause of neonatal seizures.

Hypoglycemia — Hypoglycemia should be corrected immediately with a 10 percent glucose solution given intravenously at 2 mL/kg. Maintenance glucose infusion can be given to a maximum of 8 mg/kg per minute. A detailed review of the evaluation and treatment of hypoglycemia in infants is discussed separately. While hypoglycemia is a reversible cause of neonatal seizures, severe hypoglycemia can result in brain injury and risk for both refractory neonatal seizures and postneonatal epilepsy. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

Hypocalcemia — Hypocalcemia associated with severe neuromuscular irritability or seizures is treated with 10 percent calcium gluconate (100 mg/kg or 1 mL/kg by intravenous [IV] infusion). The solution is infused over 5 to 10 minutes while the heart rate and infusion site are monitored. The dose can be repeated in 10 minutes if no response occurs. Alternatively, calcium chloride (20 mg/kg or 0.2 mL/kg) can be given. After acute treatment, maintenance calcium gluconate should be added to the IV solution. The etiology, evaluation, and treatment of hypocalcemia in neonates are discussed in detail separately. (See "Neonatal hypocalcemia", section on 'Management'.)

Hypomagnesemia — Neonatal hypomagnesemia is often associated with hypocalcemia, although it can occur alone. The treatment is 50 percent solution of magnesium sulfate given by intramuscular injection at 0.25 mL/kg or 125 mg/kg. The same dose can be repeated every 12 hours until normomagnesemia is achieved. (See "Neonatal hypocalcemia", section on 'Correction of hypomagnesemia'.)

Cofactor and vitamin deficiencies — Although inborn errors of metabolism are rare, seizures are a common manifestation of many of these disorders, especially in the neonatal period. It is important to recognize such disorders early, since cofactor or vitamin supplementation and other disease-modifying therapies are available for some. The approach to recognition and treatment of cofactor-responsive neonatal seizures is summarized in the algorithm (algorithm 1). (See "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies'.)

Pyridoxine or PLP responsive seizures — Pyridoxine-dependent epilepsy (PDE) due to antiquitin (ATQ) deficiency and the related disorder, pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, are rare but treatable genetic causes of medically refractory neonatal seizures.

●Therapeutic trials – Sequential therapeutic trials of pyridoxine (100 mg IV injections, repeated every 5 to 15 minutes up to a maximum of 500 mg with continuous EEG monitoring, or 15 to 30 mg/kg per day orally in three divided doses) and pyridoxal 5'-phosphate (PLP, the active form of pyridoxine [vitamin B6]) should be given to neonates with seizures unresponsive to conventional ASMs, particularly if the cause of the seizures is not known (algorithm 1).

Trials of IV pyridoxine should be performed with EEG and close cardiopulmonary monitoring, as there is a risk of apnea with pyridoxine, particularly when given IV. If there is no response to pyridoxine or PLP, leucovorin (2.5 mg IV) may be administered, since some cases of ATQ deficiency respond better to leucovorin (folinic acid) than pyridoxine [4].

●Further evaluation – The results of one case series caution that EEG response alone to pyridoxine IV does not definitively identify (nor does lack of initial response exclude) PDE [5,6]. Genetic analysis of the ALDH7A1 gene (alone, or as part of a multigene panel) can confirm the diagnosis of PDE in patients with evidence of pyridoxine or leucovorin responsiveness [7]. An alternative diagnostic approach is biochemical evaluation including measurement of urine alpha-aminoadipic semialdehyde (alpha-AASA) and/or plasma pipecolic acid. Elevation of alpha-AASA is informative in both treated and untreated states [8,9]. If not already evaluated as part of a gene panel, genetic testing for PNPO pathogenic variants is suggested in patients with either pyridoxine- or PLP-responsive seizures with negative testing for ALDH7A1 pathogenic variants or who have normal alpha-AASA levels.

●Long-term supplementation – Patients with PDE or PNPO deficiency should receive chronic supplementation with pyridoxine and/or leucovorin, respectively, and may also benefit from a lysine-restricted diet supplemented with lysine-free amino acid formula [10-13]. Long-term treatment doses of pyridoxine vary between 15 and 30 mg/kg/day for infants [10]. Some commercially available lysine-free formulas are also free of tryptophan, in which case tryptophan should be supplemented. Long-term treatment with high doses of pyridoxine can result in peripheral neuropathy, but this is balanced against the need for treatment to prevent seizures and optimize brain development.

Infants with PNPO deficiency should receive chronic oral PLP supplementation [10].

Biotinidase deficiency — Biotinidase deficiency due to pathogenic variants in the biotinidase gene may result in medically refractory neonatal seizures that are responsive to oral biotin supplementation. In states where biotinidase enzyme activity is not included in the newborn screening panel, a trial of biotin may be considered in addition to pyridoxine, PLP, and/or leucovorin (algorithm 1).

Molybdenum cofactor deficiency — Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disorder that results from one of several single gene defects in the biosynthetic pathway of molybdenum cofactor. Approximately two-thirds of patients have MoCD type A, with inability to synthesize the first intermediate in the pathway, cyclic pyranopterin monophosphate (cPMP), and the toxic accumulation of sulfites in blood and urine. Most neonates present with exaggerated startle, lethargy, intractable seizures, and autonomic dysfunction. (See "Etiology and prognosis of neonatal seizures", section on 'Cofactor and vitamin deficiencies'.)

●Fosdenopterin – Supplementation of cPMP by daily IV infusions is a promising therapy in patients with MoCD type A (but not type B), with the potential to greatly improve neurodevelopmental outcomes when started sufficiently early and continued chronically [14-17].

In 2021, the US Food and Drug Administration (FDA) approved fosdenopterin, a cPMP substrate replacement therapy, to reduce the risk of mortality for patients with MoCD type A [18]. Approval was based on a combined analysis of several small studies showing an increased survival probability at three years for 13 treated patients compared with 18 matched, untreated patients (84 versus 55 percent).

Fosdenopterin is given daily by IV injection; the dose is based upon weight and age [19]. The most frequent adverse events include complications related to the IV catheter, fever, respiratory infections, vomiting, gastroenteritis, and diarrhea. Because of the potential for photosensitivity, treated patients and caregivers are advised to avoid patient exposure to sunlight and to use protective measures when exposed to the sun.

ANTISEIZURE MEDICATION THERAPY — The use of antiseizure medications (ASMs) for neonates with seizures will be reviewed. Initiating therapy, selecting appropriate medication, and stopping or continuing therapy are the main decisions involved. The approach below is based on 2023 draft guidelines from the International League Against Epilepsy (ILAE), clinical experience, observational studies, and a limited number of randomized trials [1,20,21].

Decision to start ASM therapy — After initial management of airway and cardiovascular support and the identification and institution of etiology-specific therapy, the next decision is whether to initiate ASM therapy. Factors that must be considered include seizure duration and severity as well as seizure etiology:

●Neonates with brief seizures due to transient, reversible electrolyte or glucose abnormalities do not require immediate treatment with ASM; instead, they require immediate correction of the electrolyte or glucose abnormalities, with careful monitoring for recurrence.

●Seizures due to other etiologies, particularly if they are prolonged, are properly treated urgently with ASM (ie, without delay).

The decision to start acute therapy should come with a predefined, expected endpoint of treatment. Experts advocate the treatment of both clinical and subclinical electrographic seizures, since the only difference between the two types is their cortical distribution [22].

Role of continuous EEG monitoring — We employ continuous EEG monitoring to diagnose neonatal seizures and continue EEG monitoring until the patient is seizure free for 24 hours. If continuous EEG monitoring is not available, then reduced montage EEG (usually amplitude-integrated EEG [aEEG]) can be used to help guide assessment and treatment. In settings without access to continuous EEG monitoring, diagnostic certainty for neonatal seizures varies according to the available resources (EEG, aEEG, or observation by experienced personnel) and seizure semiology (algorithm 2) [22]. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Diagnosis'.)

EEG is critical in the diagnosis and treatment of neonatal seizures because most neonatal seizures have no clinical correlates, and distinguishing neonatal seizures from other abnormal movements is difficult (algorithm 3) [1]. Electrographic-only (ie, subclinical) seizures have similar pathogenesis and similar prognostic and treatment implications compared with electroclinical seizures. Conversely, paroxysmal clinical events without any EEG correlate are not seizures and so should not be treated with ASMs. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Diagnosis'.)

Since most abnormal movements are not neonatal seizures and most neonatal seizures are subclinical, using EEG to guide treatment of neonatal seizures limits unnecessary exposure to ASMs for those whose events are not seizures and avoids undertreatment of those with subtle or subclinical seizures. However, no clinical data prove definitively that this approach improves long-term outcomes. The role of continuous EEG monitoring in directing treatment is highlighted in a guideline from the American Clinical Neurophysiology Society [23] and by the ILAE [22]. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy".)

An historical approach was to treat clinically evident seizures, with or without EEG confirmation of the diagnosis. This approach is problematic because it does not accurately or adequately treat true seizures; infants whose clinical events have no EEG correlate (ie, are not truly seizures) will be exposed unnecessarily to potentially harmful medication, while neonates with clinically subtle or truly subclinical seizures will be insufficiently treated [24].

First-line ASM therapy — An approach to first-line and second-line ASM selection and dosing based on seizure frequency and individual patient characteristics is summarized in the algorithm (algorithm 4). The traditional strategy is to acutely treat seizures with a medication that can be subsequently given as maintenance therapy.

Phenobarbital for most etiologies — Phenobarbital is first-line ASM therapy for most etiologies of neonatal seizures, including neonatal encephalopathy (and associated hypoxic-ischemic encephalopathy [HIE]), arterial ischemic stroke, intracranial hemorrhage, central nervous system (CNS) infection, and seizures without an identified etiology [1]. Acute treatment can also be started with a short-acting benzodiazepine if a delay is likely prior to availability and administration of phenobarbital. (See 'ASM options for refractory seizures' below.)

●Phenobarbital dosing – The initial dose of phenobarbital is typically 20 mg/kg by intravenous [IV] infusion, followed by a maintenance dose of 4 to 6 mg/kg per day in two divided doses. If seizures do not resolve after the first loading dose, repeat boluses of 10 to 20 mg/kg should be given, up to a total dose of 50 mg/kg over 24 hours (algorithm 4). The second dose (20 mg/kg) can be given one hour after the loading dose, and the third dose (10 mg/kg) after another hour. The second and third doses can be given sooner for neonates with frequent seizures or status epilepticus (see 'Frequent seizures and status epilepticus' below). If there is no benefit at all after reaching 40 mg/kg, it is practical to prepare for adding another ASM. (See 'ASM options for refractory seizures' below.)

Phenobarbital is eliminated by the liver and kidney; thus, infants with impaired hepatic or renal function, such as those with HIE, may have a reduced rate of elimination. Yet, standard phenobarbital loading doses of 20 mg/kg are still typically appropriate in this clinical scenario. Although therapeutic hypothermia treatment may reduce clearance of phenobarbital marginally, no a priori change in loading or initial maintenance dosing is required [25,26].

The half-life of phenobarbital is greater in premature compared with term infants and longer in the first month of life compared with older ages in term infants. Thus, standard phenobarbital dosing in premature infants has the potential for higher serum levels and resultant toxicity. Nevertheless, standard phenobarbital loading doses of 20 mg/kg are still typically appropriate in this clinical scenario as well, with additional loading or maintenance dosing adjusted based on response to treatment and any clinically apparent side effects. As the infant becomes older, identical daily maintenance doses may result in lower serum levels and create the potential for breakthrough seizures with no other change in the infant's clinical condition. Overall, monitoring trends of serum levels rather than day-to-day fluctuations are more useful in management of phenobarbital therapy [27-29].

●Rationale and evidence supporting phenobarbital as first line – Phenobarbital has long been used as first-line therapy for seizures in neonates, and it remains the most commonly used agent in this setting [2,30-34]. The next most frequently used first-line agent is fosphenytoin. However, enteral absorption of phenytoin is limited for newborns, and long-term maintenance dosing of phenytoin is challenging.

Limited evidence supports phenobarbital as the first-line agent for neonatal seizure treatment. Neither phenobarbital nor phenytoin appears to be more effective than the other, and neither is completely effective. This was demonstrated in a landmark randomized trial published in 1999 that randomly assigned 59 infants with EEG-confirmed seizures to receive either phenobarbital or phenytoin [35]. Seizures were controlled in less than half of the infants (43 percent with phenobarbital and 45 percent with phenytoin); seizure severity was a better predictor of treatment success than the assigned treatment.

The NEOLEV2 trial, published in 2020, randomly assigned 83 neonates to phenobarbital or levetiracetam as first-line treatment for EEG-confirmed neonatal seizures of any cause [21]. Complete seizure freedom for 24 hours, determined by continuous EEG monitoring, was far more likely for patients assigned to phenobarbital compared with levetiracetam (80 versus 28 percent, absolute risk reduction 52 percent, relative risk 0.35, 95% CI 0.22-0.56]. The greater efficacy of phenobarbital in the NEOLEV2 trial compared with the efficacy of phenobarbital in the earlier trial discussed above [35] was hypothesized to be due to the rapid time to treatment, facilitated by real-time remote review of the neonatal EEG [21].

Based on the NEOLEV2 study, we suggest that levetiracetam should not be administered as a first-line agent [21]. This recommendation is in accordance with the ILAE guideline [1].

There are few data to guide second-line treatment decisions if phenobarbital fails to control the seizures. Neonatal seizures refractory to phenobarbital often respond poorly to second-line ASMs. This observation is illustrated by results of a small trial in which neonates whose seizures did not respond to phenobarbital (11 of 22) were randomly assigned to second-line therapy with either clonazepam (n = 3), midazolam (n = 3), or lidocaine (n = 5) [36]. No response was seen in the neonates treated with clonazepam or midazolam. Three of five responded to lidocaine, two neonates became seizure free with 4 mg/kg per hour of lidocaine, and one had an 80 percent reduction in seizure burden. All 11 neonates for whom phenobarbital failed to control seizures had a poor neurodevelopmental outcome at one year.

Sodium channel blockers for channelopathies — Phenytoin/fosphenytoin or carbamazepine (sodium channel blockers) are first-line ASMs for neonates with a family history of epilepsy due to a channelopathy and a clinical course consistent with self-limited familial neonatal epilepsy (SeLNE), or for neonates with clinical or EEG findings suggestive of a channelopathy, such as SeLNE and epilepsies caused by pathogenic variants of KCNQ2, KCNQ3, or SCN2A [1]. However, in clinical practice, most neonates with these epilepsy syndromes will have received loading doses of phenobarbital before the diagnosis of a channelopathy is considered or established (and while investigation for acute provoked causes of seizures are underway). The sodium channel blocker can be started once the diagnosis is made, and phenobarbital can be stopped without a taper. (See "Overview of neonatal epilepsy syndromes".)

●Phenytoin/fosphenytoin dosing – Dosing of these ASMs is described below. (See 'Phenytoin/fosphenytoin' below.)

●Carbamazepine dosing – The starting dose of oral carbamazepine suspension is 10 to 20 mg/kg per day in divided doses two times daily. In the acute phase, the dose can be titrated daily, with maximum daily doses usually not exceeding 35 mg/kg per day.

Assessing response to acute therapy — Best practice consists of urgent administration of ASM therapy with expedited dose escalation until seizures are controlled, with the first medication given in sufficient doses to achieve seizure freedom and/or serum levels in the high therapeutic range and/or the maximum tolerated dose. (See 'Phenobarbital for most etiologies' above.)

If seizure freedom is not achieved despite optimal dosing of first-line ASM, this is followed by additional medications, titrated to effect. (See 'ASM options for refractory seizures' below.)

●Consider electroclinical dissociation – Neonates with electroclinical seizures may have electroclinical dissociation, or uncoupling, after ASM treatment initiation. In this scenario, the clinical signs vanish but the electrographic seizures persist [37,38]. Ideal management therefore includes EEG confirmation of treatment response, which is defined most precisely by resolution of electrographic seizures.

●Reconsider the etiology – The etiology should be reconsidered if the seizures do not respond as expected. As an example, neonatal seizures related to HIE should resolve within a few days; if not, alternative etiologies such as a metabolic disorder or neonatal-onset epilepsy should be considered.

●Feasibility of complete seizure control – In some cases, seizures cannot be completely controlled with standard treatment, and the risks of adverse effects must be weighed against the potential benefit of complete seizure control. The etiology of the seizures is a major factor in this level of decision-making (eg, a target of complete seizure control may be appropriate for a neonate with HIE but might be unreasonable for a newborn with lissencephaly).

ASM options for refractory seizures

Choice of ASM is individualized — Second-line ASMs are indicated for infants who continue to have seizures despite first-line therapy [1]. Choice of a second-line ASM must be individualized, as efficacy data are derived primarily from case series and not from randomized trials. Factors to consider when selecting an agent include seizure etiology and severity, the adverse effect profile of the drug, respiratory and cardiovascular stability of the patient, and the presence of cardiac, renal, or hepatic dysfunction (algorithm 4).

●Most seizure etiologies – For most causes of seizures, including neonatal encephalopathy (and associated HIE), arterial ischemic stroke, intracranial hemorrhage, and CNS infection, second-line ASMs are [1]:

•Phenytoin/fosphenytoin (see 'Phenytoin/fosphenytoin' below)

•Levetiracetam (see 'Levetiracetam' below)

•Lidocaine (see 'Lidocaine' below)

•Midazolam (see 'Midazolam' below)

In practice, we typically continue phenobarbital temporarily when adding a second-line ASM. To avoid side effects from polypharmacy and complex drug interactions as medications are added, we discontinue those that were ineffective at controlling the seizures. One exception is that phenobarbital should be maintained if lidocaine is started, since the lidocaine infusion will be given for <48 hours.

●Channelopathies – Phenytoin/fosphenytoin or carbamazepine (sodium channel blockers) are preferred ASMs for neonates with clinical or EEG findings suggestive of a channelopathy, such as SeLNE [1]. Most of these neonates will have received phenobarbital as a first-line agent before a genetic test result confirms the diagnosis. Once the diagnosis is confirmed, the phenobarbital can be stopped without a taper when the sodium channel blocker is started. (See "Overview of neonatal epilepsy syndromes", section on 'Self-limited (familial) neonatal syndromes'.)

●Cardiac disorder – Based on expert consensus, levetiracetam is preferred second-line ASM for neonates with cardiac disorders [1]. (See 'Levetiracetam' below.)

●Vitamin B6-dependent epilepsy – Pyridoxine and pyridoxal 5'-phosphate (PLP) trials (as add-on to ASM therapy) are indicated for neonates with clinical or EEG findings suggestive of pyridoxine-dependent (ALDH7A1) developmental and epileptic encephalopathy (PD-DEE) or the related disorder, pyridoxamine 5'-phosphate oxidase deficiency (PNPO) developmental and epileptic encephalopathy (P5PD-DEE) [1]. (See "Overview of neonatal epilepsy syndromes", section on 'PD-DEE and P5PD-DEE' and 'Cofactor and vitamin deficiencies' above.)

●Unknown cause of seizures – Pyridoxine and PLP trials (as add-on to ASM therapy) are also suggested for neonates with seizures of unknown cause that are unresponsive to standard ASM therapy [1]. (See 'Cofactor and vitamin deficiencies' above.)

Newer ASMs are increasingly prescribed for neonatal seizures [39,40]. This trend has been driven by incomplete efficacy of more standard agents and concerns about their potential neurotoxicity. However, there is no high-quality evidence of greater efficacy or lower adverse event rates with these agents in neonates. Levetiracetam in particular has been used with increasing frequency, likely due to its readily available IV formulation and favorable side effect profile among older children and adults. Practice has changed with publication of the NEOLEV2 trial, as the results did not support efficacy of this drug at doses of 40 to 60 mg/kg for first- or second-line treatment [21].

Phenytoin/fosphenytoin — The prodrug fosphenytoin is the preferred formulation of phenytoin for rapid IV loading based on a lower risk of side effects, including a reduced risk of local irritation at the site of infusion. The typical loading dose of fosphenytoin is 20 mg phenytoin equivalents (PE) per kg IV, at a rate of 3 mg PE/kg per minute. Cardiac monitoring is required, as hypotension and cardiac arrhythmias remain a risk.

Pharmacologic characteristics of phenytoin include its nonlinear pharmacokinetics, variable rate of hepatic metabolism, decreased elimination rates during the first weeks of life, and variable bioavailability of the drug with various generic preparations [41,42]. Phenytoin is protein bound; thus, measuring both free and total levels may be helpful for critically ill neonates with low albumin levels. In addition, a redistribution of phenytoin results in a drop in brain concentrations after the first dose. Finally, phenytoin has poor oral bioavailability in infants. Thus, phenytoin use requires individualization of dosing after initiation of therapy and should generally be avoided as a chronic maintenance medication for newborns.

Levetiracetam — When used in the case of refractory neonatal seizures, we suggest a levetiracetam loading dose of 60 mg/kg IV, followed by a maintenance dose of 60 mg/kg/day IV in three divided doses [43,44]. The pharmacokinetic and safety profile of levetiracetam for neonatal seizure treatment is not fully understood and may differ from older children and adults [43-46]. It follows that the doses of levetiracetam reported in the literature are very broad (10 to 60 mg/kg/day) [45-47].

Importantly, in the NEOLEV2 trial, adding levetiracetam 40 mg/kg did not control seizures for any of the six neonates whose seizures persisted despite two loading doses of phenobarbital, and an additional dose of levetiracetam 20 mg/kg was associated with seizure cessation in only one of the six neonates [21]. Conversely, adding phenobarbital 20 mg/kg when seizures persisted after levetiracetam resulted in seizure control for 14 of 37 infants (38 percent). Thus, levetiracetam loading doses of 40 to 60 mg/kg are unlikely to provide immediate seizure control as first- or second-line treatment for neonates who have persistent seizures after phenobarbital administration.

Levetiracetam may still be an acceptable option in neonates with cardiac or liver dysfunction. Additionally, levetiracetam may reduce neuronal apoptosis in models of neonatal hypoxic-ischemic brain injury [48,49] and might have neuroprotective effects [50], though this has not been shown in human trials.

Lidocaine — Lidocaine is typically administered as an initial bolus dose (2 mg/kg over 10 minutes), followed by a continuous infusion of 7 mg/kg/hour for 4 hours and decreasing the dose by 50 percent every 12 hours for the next 24 hours (ie, 3.5 mg/kg/hour for 12 hours, then 1.75 mg/kg/hour for 12 hours) (table 2) [51]. To minimize the risk of iatrogenic arrhythmia, the maximum lidocaine infusion time is 48 hours, but the most recent publications indicate that less than 30 hours is preferable [51,52].

IV lidocaine administration may be arrhythmogenic and requires continuous noninvasive monitoring of electrocardiogram (ECG), heart rate, and blood pressure. Additionally, lidocaine is contraindicated in infants with congenital heart disease and in those who have already received phenytoin/fosphenytoin, due to the heightened risk for arrhythmia [53].

The continuous infusion must be adjusted for neonates treated with therapeutic hypothermia, as hypothermia decreases lidocaine clearance [51]. In this setting, and in infants with low body weight (<2.5 kg), slightly lower doses of lidocaine should be used, although the optimal approach has not been established. Proposed dosing of lidocaine under both normothermic and hypothermic conditions is presented in the table (table 2) [51].

IV lidocaine is an effective agent for neonatal seizures in selected patients. In cases of continued, EEG-confirmed status epilepticus despite high doses of phenobarbital, IV lidocaine may be the preferred second-line drug, provided there are no contraindications to its use (eg, congenital heart disease, pretreatment with fosphenytoin/phenytoin) (algorithm 4).

In a retrospective study of over 400 full-term (n = 319) and preterm (n = 94) infants with neonatal seizures diagnosed by aEEG who received lidocaine as a second- or third-line agent, the overall response rate was 71 percent [51]. Response rates were higher in full-term than preterm infants (76 versus 55 percent). In full-term infants, lidocaine was associated with a higher response rate compared with midazolam in the second-line setting (21 versus 13 percent).

Midazolam — Continuous infusion of midazolam is an option in neonates with status epilepticus, provided a secure airway has been established.

Midazolam is typically given as a bolus of 150 mcg/kg (0.15 mg/kg) followed by continuous infusion beginning at 1 mcg/kg per minute (0.06 mg/kg per hour) [1,54]. It is then titrated upward to effect in steps of 1 mcg/kg per minute to a maximum of 6.7 mcg/kg per minute (0.4 mg/kg per hour), although doses up to 18 mcg/kg per minute (1.08 mg/kg per hour) have been used without serious adverse effects [1,54].

Aside from sedation and the need for assisted ventilation, midazolam is associated with minimal cardiovascular effects.

A nonrandomized retrospective study found that midazolam was rapidly effective in 13 neonates (10 with status epilepticus) who had electrographic seizures refractory to phenobarbital and phenytoin [54]. Midazolam was given as a bolus of 0.15 mg/kg followed by continuous infusion beginning at 1 mcg/kg per minute and increasing by 0.5 to 1 mcg/kg per minute every two minutes to electrographic seizure control or to a maximum of 18 mcg/kg per minute. Neonates with status epilepticus were given a repeat bolus of midazolam 0.10 to 0.15 mg/kg if status epilepticus persisted 15 to 30 minutes after the initial bolus. While these results appear promising, randomized clinical trial data are needed to confirm that midazolam is effective for neonatal seizures, especially since midazolam was ineffective in a small, randomized clinical trial [36].

Bumetanide — Until further data are available, routine clinical use of bumetanide as an adjuvant treatment for neonatal seizures is not recommended.

Interest in bumetanide arose from a body of research on neuronal chloride homeostasis, which may explain, at least in part, why phenobarbital is often incompletely effective in newborns [55,56]. The neuronal chloride gradient in mature neurons is maintained by the activity of potassium-chloride cotransporter 2 (KCC2) channels, which decrease resting intracellular chloride concentrations. When gamma-aminobutyric acid (GABA) receptors are activated (eg, by medications such as phenobarbital), the cell is hyperpolarized due to chloride influx. In immature neurons, KCC2 is underexpressed, whereas sodium-potassium-chloride transporter 1 (NKCC1) channels, which increase intracellular chloride concentrations, are prevalent. The result is a reversed neuronal chloride gradient, such that activation of GABA receptors can paradoxically depolarize the neuron.

Bumetanide is a diuretic that acts on NKCC1 channels and could, in theory, be used as rational polytherapy in combination with phenobarbital. In animal models [57,58] and a human case study [59], cotreatment with bumetanide and phenobarbital appeared to enhance treatment effects. An open-label phase I/II trial of bumetanide combined with phenobarbital was closed early due to limited efficacy and important safety concerns, including 3 of 11 surviving infants (27 percent) with significant hearing impairment [60]. However, results from a small, double-blind, randomized controlled trial suggest that bumetanide may be a safe and effective second-line treatment. Seizure burden was reduced, particularly among infants with the highest baseline seizure burden, after combination treatment with phenobarbital and bumetanide. Hearing impairment was observed in 2 of 26 patients (8 percent) treated with bumetanide [61]. The cause of hearing impairment for the five affected infants in these two trials was confounded by the presence of additional risk factors, including HIE in all five and gentamicin treatment in four [60,61]; these findings should be viewed in the context of the approximately 10 percent risk for hearing impairment reported among survivors of HIE [62].

Frequent seizures and status epilepticus — The approach to treatment for frequent recurrent neonatal seizures is identical to that of status epilepticus (algorithm 5). ASMs are titrated efficiently to maximal tolerated doses or until the seizures stop. For neonates who present with or progress to frequent seizures or status epilepticus, first-line treatment (if not already given) is phenobarbital 20 to 30 mg/kg by IV infusion, followed by a maintenance dose of 4 to 6 mg/kg per day in two divided doses. Continuous EEG monitoring is needed to determine if electrographic seizures are controlled. If seizures do not resolve after the first loading dose, repeat boluses of phenobarbital 10 to 20 mg/kg are given with a goal phenobarbital level of approximately 50 mcg/mL or a total 24-hour dose of 50 mg/kg.

If seizures continue, the next steps are guided by cardiac status and prior ASM treatment (algorithm 5):

●Cardiovascular abnormalities or instability – For patients with cardiovascular abnormalities or instability, we continue phenobarbital and give midazolam as a bolus of 0.15 mg/kg followed by continuous infusion beginning at 0.6 mg/kg per hour, weaning gradually after 24 hours of seizure freedom. (See 'Midazolam' above.)

Levetiracetam is an alternative to midazolam, starting with a bolus of 60 mg/kg IV, followed by a maintenance dose of 60 mg/kg per day (IV or oral) in three divided doses. (See 'Levetiracetam' above.)

●No cardiovascular concerns and no phenytoin/fosphenytoin – For patients with status epilepticus who do not have cardiovascular abnormalities or instability and have not already received phenytoin or fosphenytoin, we continue phenobarbital and give IV lidocaine with a bolus (2 mg/kg over 10 minutes) followed by a continuous infusion of 7 mg/kg per hour for four hours and decreasing the dose by 50 percent every 12 hours for the next 24 hours (ie, 3.5 mg/kg per hour for 12 hours, then 1.75 mg/kg per hour for 12 hours) (table 2). IV lidocaine administration may be arrhythmogenic and is contraindicated in infants with congenital heart disease and in those who have already received phenytoin/fosphenytoin, due to the heightened risk for arrhythmia. (See 'Lidocaine' above.)

If lidocaine is not available, we consider a loading dose of 20 mg/kg of fosphenytoin (or phenytoin) in this clinical scenario.

●No cardiovascular concerns but already treated with phenytoin/fosphenytoin – For patients without cardiovascular abnormalities or instability who have already been treated with phenytoin or fosphenytoin, we treat with levetiracetam starting with a bolus of 60 mg/kg IV, followed by a maintenance dose of 60 mg/kg per day (IV or oral) in three divided doses. (See 'Levetiracetam' above.)

Duration of therapy — ASM treatment duration should be guided by the neonatal seizure etiology. As summarized here, most neonates with acute provoked seizures can safely discontinue all ASMs prior to hospital discharge. Conversely, most infants with neonatal-onset epilepsy require long-term treatment.

Acute provoked seizures — Acute provoked (symptomatic) seizures (table 3) are not classified as epilepsy.

●Discontinue ASMs for infants with seizure freedom – For neonates with acute provoked seizures, we generally discontinue ASMs without a taper after 72 hours of seizure freedom and before discharge to home [1]. In a prospective, multicenter study, 303 children with neonatal seizures attributed to an acute provoked cause (ie, HIE, ischemic stroke, intracranial hemorrhage, or other acute brain injury) were evaluated according to the duration of ASM treatment, which was maintained at hospital discharge for 64 percent of neonates and discontinued for the remainder [63]. The study was designed and powered to detect noninferiority. At age 24 months, after adjusting for propensity to maintain medications, there was no difference between the ASM continuation and discontinuation groups for the outcomes of functional neurodevelopment or postneonatal epilepsy development. The results were not different for neonates with severely abnormal EEG patterns or abnormal neurologic examinations. In this study, every infant who developed postneonatal epilepsy before age four months had their ASM maintained after discharge; thus, maintained medication does not appear to prevent postneonatal epilepsy. These findings support discontinuation of ASM before hospital discharge for all neonates with acute provoked seizures.

●Close follow-up for infants at increased risk of epilepsy – Infants with three or more days of EEG-confirmed neonatal seizures, or a severely abnormal EEG background pattern, or an abnormal neurologic examination at the time of hospital discharge are at increased risk for postneonatal epilepsy. These infants can safely be discharged without ASM but require close follow-up [1,64,65]. Parents of infants at high risk should be taught the signs of infantile spasms and other seizure types so they can seek urgent assessment and treatment if their child develops postneonatal epilepsy.

Other experts express caution about discontinuing ASM for infants presenting with provoked seizures who have significant abnormalities on neurologic examination, EEG, or brain magnetic resonance imaging (MRI), notwithstanding seizure freedom. Although ASM discontinuation in this setting is a consensus-based recommendation from the ILAE [1], the evidence supporting it comes primarily from a prospective observational study with propensity-weighted analyses rather than a randomized controlled trial [63].

Despite this caution, there are several potential downsides and limitations to continuing ASM in this situation:

•Continuing ASMs has not been shown to improve neurodevelopmental outcome. Although nonrandomized and observational, the study of 303 children with neonatal seizures attributed to an acute provoked cause was prospective and designed and powered to evaluate for noninferiority, and it found that ASM continuation was not associated with neurodevelopmental outcome [63].

•The same study found that prophylactic ASM treatment was not associated with reduced risk for postneonatal epilepsy or delay in the onset of epilepsy; children with the earliest onset of epilepsy developed epilepsy despite ASM maintenance; all of those with epilepsy by four months were discharged home on ASM [63].

•Prolonged ASM exposure increases the risk of harm from adverse effects of medications and the burden of therapy.

•For the treatment of infantile epilepsy with onset at <12 months of age, levetiracetam is preferred rather than phenobarbital [66]. However, for the treatment of neonatal seizures, levetiracetam is not recommended [1,21]. Most babies with provoked seizures who are maintained on ASM at hospital discharge go home on phenobarbital, which is not preferred if they go on to develop postneonatal epilepsy.

•Greater than one-third of early-onset epilepsy in neonates with acute provoked seizures is infantile epileptic spasms. Infantile epileptic spasms do not respond to phenobarbital or to levetiracetam [67,68]. Thus, discharging babies on either of these ASMs will not help prevent or treat infantile epileptic spasm syndrome. (See "Infantile epileptic spasms syndrome: Management and prognosis".)

Neonatal epilepsy — In contrast with acute provoked seizures, newborns with neonatal-onset epilepsy syndromes (table 3) will have ongoing risk for recurrent seizures after the neonatal period and should be maintained on ASM. Chronic therapy should be tailored to the individual infant. Maintenance doses of phenobarbital are often prescribed (3 to 6 mg/kg per day), and serum levels may be monitored. However, for neonates with epilepsies suspected to be caused by channelopathies (eg, pathogenic variants of KCNQ2, KCNQ3, or SCN2A), several reports suggest that carbamazepine or, by extension, oxcarbazepine, may be effective [69-71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Expedited treatment – Neonatal seizures are a neurologic emergency. Treatment that lowers the neonatal seizure burden may be associated with improved outcomes. All neonatal units should use a local or national pathway for the treatment of neonatal seizures to expedite evaluation and treatment. Neurology consultation is advised as soon as neonatal seizures are suspected. (See 'Expedited treatment' above.)

●Etiologic therapy – Neonatal seizures should prompt an immediate evaluation to determine cause and to institute etiology-specific therapy. Treatment of the underlying cause (for metabolic disorders, central nervous system or systemic infection, neonatal encephalopathy, and cofactor and vitamin deficiencies) is critical since it may prevent further brain injury. Also, neonatal seizures may not be effectively controlled with antiseizure medication (ASM) unless their underlying cause is treated. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Etiologic evaluation' and 'Etiologic therapy' above.)

●Who should be treated with ASM? – Seizure etiology, seizure duration, and seizure severity must be considered in deciding upon ASM therapy. Brief seizures due to transient, reversible electrolyte or glucose abnormalities do not require immediate treatment with ASM, while seizures due to other etiologies, particularly if they are prolonged, are properly treated urgently with ASM. We employ continuous EEG monitoring with ASM treatment until the patient is seizure free for 24 hours. (See 'Decision to start ASM therapy' above and 'Role of continuous EEG monitoring' above.)

●First-line ASM – For most etiologies of neonatal seizures, we suggest first-line treatment with phenobarbital rather than phenytoin or levetiracetam (Grade 2C), in accordance with international guidelines. Phenobarbital and phenytoin were equally effective in a small, randomized trial, but maintenance oral dosing of phenytoin in the newborn is challenging. In another randomized trial, phenobarbital was much more effective than levetiracetam for short-term seizure control as a first- and second-line agent. Dosing schedules are listed in the algorithm (algorithm 4). For neonates with a family history or clinical or EEG findings suggestive of a channelopathy, fosphenytoin or carbamazepine (sodium channel blockers) are first-line ASM choices. (See 'First-line ASM therapy' above.)

●Response to acute therapy – Best practice consists of continuing acute ASM therapy until all seizures (clinical and EEG seizures) are controlled, with the first medication given in doses sufficient to achieve serum levels in the high therapeutic range or to the maximum tolerated dose before additional medications are added. Ideal management includes EEG confirmation of treatment response, which is defined most precisely by resolution of electrographic seizures. (See 'Assessing response to acute therapy' above.)

●Refractory seizures and status epilepticus – Neonatal seizures refractory to phenobarbital often respond poorly to second-line ASMs. The approach to treatment for frequent recurrent neonatal seizures is identical to that of status epilepticus (algorithm 5). ASMs are titrated efficiently to maximal tolerated doses or until the seizures stop.

•Most seizure etiologies – The most commonly used ASMs for treatment-resistant neonatal seizures are phenytoin/fosphenytoin, levetiracetam, lidocaine, and midazolam. Factors to consider when selecting an ASM include seizure severity, the side effect profile of the drug, respiratory and cardiovascular stability of the patient, and the presence of cardiac, renal, or hepatic dysfunction (algorithm 4). Levetiracetam is preferred for neonates with cardiac abnormalities. (See 'ASM options for refractory seizures' above.)

•Unknown seizure etiology or suspected vitamin B6-dependent epilepsy – Pyridoxine and pyridoxal 5'-phosphate (PLP) trials (added on to ASM therapy) should be given sequentially to neonates with seizures unresponsive to conventional ASMs if the cause of the seizures is unknown (algorithm 1), and to neonates with clinical or EEG findings suggestive of vitamin B6-dependent epilepsy. (See 'Pyridoxine or PLP responsive seizures' above.)

●Duration of therapy – For neonates with acute provoked seizures, the author (following International League Against Epilepsy [ILAE] guidelines) discontinues ASMs without a taper after 72 hours of seizure freedom and prior to hospital discharge, even for neonates who have abnormal EEG patterns, brain MRI, or an abnormal neurologic examination. Infants at high risk for postneonatal epilepsy should have careful follow-up with a pediatric neurologist.

By contrast, newborns with neonatal-onset epilepsy syndromes will have ongoing risk for recurrent seizures after the neonatal period and should be maintained on ASM. (See 'Duration of therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Eli M Mizrahi, MD, who contributed to an earlier version of this topic review.