Treatment of Neonatal Seizures

Eli M. Mizrahi

Mark S. Scher

Introduction

The overall goal of treatment of neonatal seizures is to minimize brain injury that may be associated with or caused by recurrent seizures. A critical factor in the therapy of neonatal seizures is accurate diagnosis. This requires precise clinical characterization and classification of neonatal seizures and, when the electroencephalogram (EEG) is available, accurate interpretation of the ictal EEG. These will allow for the determination of the presence or absence of behaviors that can be considered neonatal seizures and, importantly, whether these clinical events can be considered epileptic or nonepileptic in origin. Overall, this provides the basis for the determination of the appropriateness of antiepileptic drug (AED) treatment.

Characterization, classification, and determination of pathophysiology have been discussed in detail in Chapter 56 and are summarized in Table 1. In this chapter, the term seizures will be utilized to refer to all clinical seizure types; the terms epileptic and nonepileptic will be used to specifically address the therapy of these types. The discussion below, for the most part, will be directed toward seizures based on their clinical characteristics. However, some aspects of the discussion will consider electrical seizure activity, either alone or in relation to clinical seizures. In these instances, EEG seizure discharges will be referred to specifically. One practical method of classifying seizures is to consider the clinical events in relationship to electrical seizure activity. Thus, electroclinical seizures are those during which both clinical and electrical seizure activity occur simultaneously, electrical-only seizures are those without clinical events, and clinical-only seizures are those that occur with no associated electrical seizure activity.

Principles of Therapy

The goal of treating neonatal seizures is to prevent long-term central nervous system (CNS) dysfunction, which may be associated with or potential sequelae of seizures. The main objectives in the therapy of neonatal seizures are the treatment of the etiologic factors that may be responsible for the seizures and the cessation of seizures of epileptic origin with either AEDs or etiology-specific therapy. These goals may be achieved in the treatment of some, but not all, infants with seizures. Etiologic factors may not be determined in all cases, and when potential causes are discovered, their precise relationship to the seizures may not be known. Some clinical seizures, because of their nonepileptic physiologic origin, may not require AEDs. Importantly, AED administration in the treatment of some epileptic seizures may not be effective in control of either the clinical or the electroencephalographic seizures. Finally, some electroencephalographic seizures may be difficult to control, despite high doses of multiple AEDs. While it is not definitively determined that either recurring seizures or acute or chronic AEDs have an adverse effect on the developing brain, there is recent evidence suggesting that both seizures and AEDs may have unwanted sequelae.

In addition to the characterization and classification of seizure type, the treatment of neonatal seizures, ideally, is based on the consideration of several interrelated factors. These include identification of the etiology of the seizure, recognition of associated risk factors, determination of pathophysiology of the seizures, assessment of the duration and the severity of the seizures, understanding the natural history of the specific seizure disorder, and assessment of the expected effects that the seizures and the AEDs may have on the developing brain. Unfortunately, information concerning all of these factors may not be complete. Despite limitations imposed by incomplete data, some rational decisions for therapy can be made by understanding these constraints and the information that is known about neonatal seizures.

Phases of Acute Therapy

Three phases of acute therapy for neonates with seizures are initial medical management, etiology-specific therapy, and AED therapy. These phases are typically individualized to each infant.

Initial Medical Management

The usual principles of general medical management, which are important in the care of older children and adults with acute seizures, also apply to neonates with seizures: maintenance of airway, adequate ventilation, and cardiovascular circulation. Neonates with seizures may be critically ill, and the frequency or duration of epileptic seizures may be consistent with the diagnosis of status epilepticus. Changes in respirations, heart rate, and blood pressure may occur (a) in association with clinical seizures, (b) as a consequence of the seizures themselves, (c) as a consequence of the etiologic or risk factors, or (d) in association with vigorous AED therapy. Thus, measures must be taken to ensure adequate ventilatory support and circulatory perfusion of neonates with seizures during initial evaluation and therapy. The anticipation that these potential autonomic changes may occur will increase the likelihood of their successful treatment.

Table 1 Classification of Neonatal Seizures Based on Electroclinical Findings

Clinical seizures with a consistent electrocortical signature (pathophysiology: epileptic)
Focal clonic
   Unifocal
   Multifocal
   Hemiconvulsive
   Axial
Focal tonic
   Asymmetric truncal posturing
   Limb posturing
   Sustained eye deviation
Myoclonic
   Generalized
   Focal
Spasms
   Flexor
   Extensor
   Mixed extensor/flexor
Clinical seizures without a consistent electrocortical signature (pathophysiology: presumed nonepileptic)
Myoclonic
   Generalized
   Focal
   Fragmentary
Generalized tonic
   Flexor
   Extensor
   Mixed extensor/flexor
Motor automatisms
   Oral-buccal-lingual movements
   Ocular signs
   Progression movements
   Complex purposeless movements
Electrical seizures without clinical seizure activity

From Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 1987;37:1837–1844; and Mizrahi EM, Kellaway P. The response of electroclinical neonatal seizures to antiepileptic drug therapy. Epilepsia. 1992;33(Suppl 3):114.

Table 2 Etiology-specific Therapy for Neonatal Seizures of Metabolic Origin

	Acute therapy	Maintenance therapy
Glucose, 10% solution	2 mL/kg IV	Up to 8 mg/kg/min IV
Calcium gluconate, 10% solution (9.4 mg of elemental Ca/mL)	2 mL/kg IV over 10 min (18 mg of elemental Ca/kg)	8 mL/kg/day IV^a (75 mg of elemental Ca/kg/day)
Magnesium sulfate, 50% solution (50 mg of elemental mg/mL)	0.25 mL/kg IM	0.25 mL/kg IM repeated every 12 h until normomagnesemia
Pyridoxine	100 mg IV
^aAfter restoration of normocalcemia, tapering dosage may help in preventing rebound hypocalcemia. Diagnosis of hypoglycemia, hypocalcemia, and hypomagnesia may vary between laboratories and is dependent on neonate’s gestational age (with preterm infants tending to tolerate lower physiologic levels). Administration of metabolic correcting solutions requires careful monitoring of infant’s systemic homeostasis, including electrocardiogram monitoring during administration of calcium.³³^,³⁴ Table from Mizrahi EM, Kellaway P. Diagnosis and Management of Neonatal Seizures. Philadelphia: Lippincott-Raven; 1998:181.

Etiology-specific Therapy

When specific causes of seizures are identified and are potentially treatable, etiology-specific therapy is initiated. The therapy of specific etiologic factors is critical as the seizures may not be responsive to standard AED therapy unless the underlying causes are successfully treated. In some cases, etiology-specific
therapy may be the only treatment needed. In other cases, AEDs must be administered because of secondary brain injury caused by the primary process. For example, metabolic etiologies such as hypocalcemia, hypomagnesemia, and hypoglycemia may be corrected, resulting in cessation of seizures and obviating the need for AEDs. On the other hand, these or other etiologies may be associated with additional underlying brain disorders; though therapies must be directed toward central nervous system (CNS) and systemic infections, AEDs may still be required for complete management.

Treatments of metabolic etiologies are listed in Table 2, including therapies for the relatively common conditions of hypocalcemia, hypomagnesemia, and hypoglycemia. For completeness, it also includes the therapy for pyridoxine deficiency. However, while pyridoxine deficiency is often cited as a treatable cause of medically refractory neonatal seizures, it is exceedingly rare and may not warrant the wide consideration it has received as an important cause of neonatal seizures. Other metabolic disorders can masquerade as hypoxic-ischemic encephalopathy with seizures and should be considered in the differential diagnosis, depending on historical, clinical examination, and laboratory findings; glycine encephalopathy, sulfite oxidase deficiency/molybdenum cofactor deficiency, glucose transporter defect deficiency syndrome, mitochondrial disorders, and folinic acid–responsive seizures are a partial listing.¹⁸

Table 3 Dosages of First-line, Second-line AEDs in the Treatment of Neonatal Seizures

Drug	Dose		Average therapeutic range	Apparent half-life
Drug	Loading	Maintenance	Average therapeutic range	Apparent half-life
Diazepam	0.25 mg/IV (bolus) 0.5 mg/kg (rectal)	May be repeated one to two times		31–54 h
Lorazepam	0.05 mg/kg (IV) (over 2–5 min)	May be repeated		31–54 h
Phenobarbital	20 mg/kg IV (up to 40 mg)	3–4 mg/kg in two doses	20–40 μg/L	100 h after days 5–7
Phenytoin	20 mg/kg IV (over 30–45 min)	3–4 mg/kg in two to four doses	15–25 μg/L	100 h (40–200)
Based on Fenichel GM. Neonatal Neurology.* 3rd ed. New York: Churchill-Livingstone; 1990; Aicardi J. Neonatal seizures. In: Epilepsy in Children. 2nd ed. International Review of Child Neurology Series. New York: Raven; 1994:217–252; and Volpe JJ. Neonatal seizures. In: Neurology of the Newborn. 4th ed. Philadelphia: WB Saunders; 2001. Table from Mizrahi EM, Kellaway P. Diagnosis and Management of Neonatal Seizures. Philadelphia: Lippincott-Raven; 1998:181.

Acute Antiepileptic Drug Therapy

First-line Antiepileptic Drug Therapy

The AEDs traditionally utilized in the acute treatment of neonatal seizures are phenobarbital, phenytoin, and a benzodiazepine (diazepam and, more recently, lorazepam) given intravenously (Table 3). The dosages utilized in the United States are phenobarbital, 20 mg/kg as a loading dose, followed by additional dosages of 10 mg/kg to achieve serum levels between 20 and 40 μg/mL; phenytoin, 20 mg/kg as a loading dose to achieve serum levels between 15 and 20 μg/mL; diazepam, 0.1–0.3 mg/kg in repeated dosages; and lorazepam, 0.05 mg/kg.⁴^,¹³^,³⁹^,⁴⁰ Acute administration of each of these AEDs may carry some risk of adverse reactions and, therefore, treated infants should be monitored closely. These adverse events may include CNS depression, hypotension, bradycardia, and respiratory depression (phenobarbital, diazepam, lorazepam), and cardiac arrhythmia (phenytoin).

Traditionally, initial dosing has been determined only by body weight of the infant. However, Painter et al.⁵¹ stressed the importance of serum protein characteristics of phenobarbital and phenytoin in initial dosing. The unbound (free) fraction of each of these drugs is pharmacologically active, and the protein-binding characteristics in neonates may vary to an extent that a uniform dosing schedule by weight only may not provide the same efficacy and safety to all infants. Thus, Painter et al. suggested that the use of in vitro binding profiles, calculated for individual neonates at risk for seizures, will allow the establishment of appropriate loading dosages of each drug and will avoid potential toxicity in individual neonates. This technique is not universally available. However, the findings do underscore the potential variability among neonates in the utilization of these drugs.

There is relative consensus of selection of specific AEDs as first- and second-line drugs: Phenobarbital is almost universally accepted as the first-line AED and phenytoin as the second-line AED.⁴ However, there is less consensus as to the use of additional AEDs if the initial drugs fail to control the seizures. Most often, a benzodiazepine (diazepam or lorazepam) may be given in these instances.

Despite the wide acceptance of phenobarbital as the first-line AED, there have been few controlled studies of the relative efficacy of various AEDs in the initial treatment of neonatal seizures. Recently, however, Painter et al.⁵³ compared the effectiveness of acute administration of phenobarbital and phenytoin in seizure control, found no significant difference, and suggested that neither is as efficacious as originally thought.

It is helpful to understand aspects of the pharmacology of phenobarbital and phenytoin in the neonate during their use in treatment of seizures. The availability of active drug given at standard doses may be altered by pathologic conditions in the sick neonates. These principles are discussed in detail elsewhere¹²^,³⁶^,³⁷^,⁵⁰ and summarized here. Phenobarbital is a weak acid and is protein bound. Infants with acidosis may have less active phenobarbital available and those with hypoalbuminemia may have greater unbound or active drug available. Both conditions may be found in sick neonates. Phenobarbital is eliminated by the liver and kidney. Thus, infants with impaired hepatic or renal function, which may occur in infants with hypoxic-ischemic encephalopathy, may have a reduced rate of elimination and, therefore, a potential for toxicity with standard dosing. There is a longer half-life of phenobarbital in preterm compared to term infants, and in term infants the half-life is reduced with chronologic age in the first month of life. Thus, in preterm infants there is a potential for higher serum levels with standard doses and the potential for toxicity. As the infant becomes older there is the potential for identical doses to result in lower serum levels, creating 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.¹⁷^,²¹^,⁵²^,⁶²

Important pharmacologic characteristics of phenytoin are described in detail elsewhere¹⁰^,¹⁶ and summarized here. These features include nonlinear pharmacokinetics, a variable rate of hepatic metabolism, a decrease in elimination rates during the first weeks of life, and a variable bioavailability of the drug with various generic preparations. In addition, there is a redistribution of the AED after the initial dose resulting in a drop in brain concentrations after the first dose. These pharmacologic characteristics indicate that phenytoin use requires individualization of dosing after the initiation of therapy.

Acute Therapy for Refractory Seizures

Because neonatal seizures may be resistant to traditionally utilized AEDs, other medications have been tried with varying success.²⁶^,²⁷^,⁴⁹^,⁵⁰ True efficacy of these agents is difficult to assess because their trials have been conducted either in an uncontrolled manner, on few patients, on infants who have already received and failed with other AEDs, on infants with only clinical seizures with electroencephalographic confirmation, or on infants utilizing oral medication (because of availability of the compound), thereby limiting the assessment of efficacy. In addition, because of the preliminary nature of these trials, little safety data are available. These AEDs have been used as alternative acute drugs or as adjuvant therapy.

The AEDs used as alternative acute therapy—and given intravenously—are midazolam,³¹^,⁵⁸ lidocaine,²⁶^,²⁷ and paraldehyde (not available in the United States).³⁵ One recent study reported success with continuous midazolam infusion in the treatment of otherwise uncontrolled neonatal seizures,³¹ although infants experienced treatment-related hypotension that was medically managed. Lidocaine has also been utilized, primarily in Europe, as an AED in neonates. It has been administered intravenously at a rate of 4 mg/kg/hr, which achieves serum levels between 3.4 and 10.5 mg/L. This drug has a narrow therapeutic range; at serum levels between 0.5 and 4 mg/L, lidocaine may act as an anticonvulsant, but at levels of
7.5 mg/L, it may act as a convulsant.²⁶^,²⁷^,⁴⁸^,⁵⁰^,⁵⁵ Boylan et al.⁹ reported limited success with lidocaine in refractory neonatal seizures. Another recent investigation⁶⁰ reported that during the use of lidocaine (initial loading dose of 2 mg/kg over 10 minutes followed by a continuous infusion of 6 mg/kg/hr), 4.8% of infants experienced a cardiac arrhythmia (all responding to lidocaine discontinuation).

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