US Pharm. 2006;11:HS-17-HS-28.

Seizures are common during childhood.^1-9 Each year, approximately 150,000 pediatric patients experience their first seizure, and 30,000 are found to have epilepsy. In addition, an estimated 4% to 10% of children have recurrent unprovoked seizures by age 18.¹

SEIZURES VERSUS EPILEPSY
Seizures are paroxysmal, time-limited changes in motor activity and/or behavior that result from abnormal electrical activity in the brain.^1,3,10 Seizures can either be localized (affecting one part of the brain) or widespread (affecting the entire brain).^1,3 Most seizures in children are provoked by somatic disorders originating outside the brain (e.g., high fever, infection, syncope, head trauma, hypoxia, toxins, cardiac arrhythmias).^3,5 The clinical appearance of a seizure depends on the location and extent of brain involvement. For example, a seizure originating in the motor cortex may cause only focal facial twitching; whereas a seizure involving the entire brain will manifest as a generalized seizure with loss of consciousness.¹¹

A child's age can serve as a clue to the possible cause of the seizure.^6,7 Children from infancy through early school-age usually develop seizures due to fever, central nervous system (CNS) infections, electrolyte and metabolic abnormalities, toxic ingestions, and CNS tumors. In contrast, adolescents and teenagers experience first-time seizures due to toxic ingestions, illicit drug or alcohol use, brain tumors, or excessive video game use.⁷

Epilepsy is defined as two or more unprovoked seizures occurring at an interval greater than 24 hours apart.^3,8 Less than one third of seizures in children are categorized as epileptic.³ Provoked seizures, such as those resulting from acute head trauma or meningitis, do not constitute epilepsy.¹¹

CLASSIFYING SEIZURES
Classification of seizure disorders has evolved considerably through the years. The terms grand mal or petit mal have been replaced by more detailed classifications based on specific clinical manifestations, extent of brain involvement (i.e., focal or generalized), and discrete clinical syndromes.⁶

Childhood epilepsy is usually classified using variations of the International Classification of Epileptic Seizures. This nomenclature delineates seizures into two categories: generalized and partial (focal) seizures.^9,11-13

Generalized Seizures
Generalized seizures originate in a bilaterally symmetric fashion within the brain and can be further classified as convulsive or nonconvulsive seizures.

Convulsive seizures include tonic, clonic, and tonic-clonic seizures. Tonic-clonic seizures are characterized by an abrupt loss of consciousness with tonic extension of the trunk and extremities (tonic phase), followed by synchronous muscle jerking (clonic phase). In some patients, only a tonic or clonic phase is apparent. During the postictal period, patients are confused and sleepy and may complain of headache. Although generalized seizures are not preceded by an aura (e.g., noxious smell or taste, unusual epigastric sensation), many patients may experience nonspecific premonitory symptoms (e.g., dizziness, irritability, anxiety).

Nonconvulsive seizures include absence, myoclonic, and atonic seizures. Absence seizures are characterized by brief attacks--usually lasting five to 10 seconds--of arrest of consciousness and movement. Some minor movements such as lip smacking or blinking may be observed. Absence seizures are not associated with postictal drowsiness. Episodes that are prolonged or have more prominent movements are termed atypical absence seizures. Myoclonic seizures are characterized by brief, single or repetitive muscle contractions of a muscle or group of muscles. Atonic seizures are characterized by a sudden, momentary loss of muscle tone or posture.¹¹

Partial Seizures

Partial seizures originate in one part of the brain and do not produce a complete loss of consciousness.¹¹ However, they may subsequently progress to a generalized seizure.^3,11,12 Partial seizures can be further subdivided into simple and complex partial seizures. Simple partial seizures do not produce alternations of consciousness, whereas complex partial seizures do.^3,11 Auras (i.e., complex partial or secondarily generalized seizures) are simple partial seizures that precede other seizure types.¹¹

CHILDHOOD EPILEPSY SEIZURES
The vast majority of epilepsy syndromes begin during infancy and childhood.² Determining which epileptic syndrome a child has is essential in establishing prognosis and providing treatment.¹¹ Common epileptic syndromes of infancy and childhood include febrile seizures, neonatal seizures, infantile spasms, Lennox-Gastaut syndrome, and childhood and juvenile absence epilepsy.

Febrile Seizures
Febrile seizures are the most common childhood seizure disorder and generally have an excellent prognosis; however, they may signify a serious underlying acute infectious disease such as sepsis or bacterial meningitis.³ Febrile seizures occur in approximately 3% of children ages 6 months to 6 years (peak age, 18 to 24 months). Most febrile seizures are "simple"--i.e., single, brief (less than 15 minutes in duration), and generalized. Approximately one third of febrile seizures are "complex" (multiple occurrences within 24 hours, prolonged, or focal).¹ Some children who experience simple febrile seizures--including those who have an initial febrile seizure before age 9 months, are developmentally delayed, have a family history of afebrile seizures, or have a preexisting neurological disorder--may be at risk for epilepsy.^1,3

Routine treatment of febrile seizures involves searching for the cause of the fever and taking measures to control the fever (e.g., with the use of antipyretics). Most children with febrile seizures do not require anticonvulsant drugs.¹ In fact, anticonvulsant prophylaxis for preventing recurrent febrile convulsions is not recommended.³

Neonatal Seizures

Neonates are at particular risk for seizures because metabolic, structural, and infectious diseases are more likely to manifest at this age than at any other.³ Neonates develop seizures primarily because of CNS infections, electrolyte abnormalities (e.g., hypocalcemia, hypoglycemia), hypoxic ischemic encephalopathy, and rarely, pyridoxine deficiency. These seizures can sometimes be a symptom of a more serious condition (e.g., birth trauma, congenital structural brain abnormalities, inborn errors of metabolism).

Unfortunately, neonatal seizures are associated with a high rate of morbidity and mortality and can be difficult to recognize. An infant experiencing neonatal seizures may display only subtle changes (e.g., apnea, sustained eye deviation, chewing, or limb bicycling movements). Overall, the rate of mental retardation and cerebral palsy in survivors of neonatal seizures is between 15% and 45%. Prognosis and treatment options are dependent on the etiology of the seizure.¹¹

Infantile Spasms (West Syndrome)
Infantile spasms present during the first year of life and consist of rapid, jackknife flexor or extensor spasms that appear in clusters. Because children with infantile spasms tend to cry and draw up their legs during an attack, an initial diagnosis of colic is common. Approximately 67% of children who have infantile spasms have an underlying CNS disorder (e.g., congenital brain malformation, tuberous sclerosis). The outcome of infantile spasms is usually poor--only about 50% of children with infantile spasms attain remission, while 90% to 95% become mentally retarded. The prognosis is substantially improved if development is normal before onset of the spasms. First-line treatment for infantile spasms consists of adrenocorticotropic hormone or prednisone.¹¹

Lennox-Gastaut Syndrome
Lennox-Gastaut syndrome is a severe form of epilepsy that is characterized by mental retardation, multiple seizure types, and a classic electroencephalographic (EEG) pattern of slow spike and wave.^9,11 While mental retardation may not be present at the onset of seizures, it eventually develops in 78% to 96% of patients. The age at onset of Lennox-Gastaut syndrome is between 1 and 6 years. This epileptic syndrome may evolve from infantile spasms--30% of patients with infantile spasms develop Lennox-Gastaut syndrome, and 20% of patients with Lennox-Gastaut syndrome have a history of infantile spasms.¹⁰ Patients with Lennox-Gastaut syndrome usually experience frequent seizures of multiple types, including atonic, atypical absence, myoclonic, tonic-clonic, and partial seizures.

First-line treatment for Lennox-Gastaut syndrome consists of valproic acid; however, this drug alone rarely controls the condition.¹¹ Other treatments for Lennox-Gastaut syndrome include lamotrigine, topiramate, felbamate, and the ketogenic diet. Felbamate was the first antiepileptic medication approved for the treatment of Lennox-Gastaut syndrome. Because felbamate can cause liver failure and aplastic anemia, it should be reserved for patients who do not adequately respond to alternative agents and whose condition is so severe that the benefits outweigh the risks.^14-17 Overall, the prognosis in patients with Lennox-Gastaut syndrome is poor.¹¹

Childhood and Juvenile Absence Epilepsy
Childhood and juvenile absence epilepsy begins most commonly between ages 4 and 12 years and is characterized by frequent recurrent absence seizures. Generalized convulsive seizures occur in up to 50% of patients. Treatment for childhood and juvenile absence epilepsy consists of ethosuximide or valproic acid (valproic acid is used in patients who have generalized tonic-clonic seizures). The prognosis for this condition is excellent--children usually outgrow this pattern and development is normal. Hyperventilation can trigger absence spells and can be used to diagnose absence epilepsy.¹¹

Status Epilepticus
Status epilepticus is characterized by more than 30 minutes of unconsciousness and continuous or intermittent seizure activity and is considered to be a true neurologic emergency.^11,13 The condition occurs more frequently in children--especially those younger than 1 year--and is associated with high morbidity and mortality. Among children, the most common precipitant of status epilepticus is febrile illness, followed by medication change, idiopathic epilepsy, metabolic derangements, and congenital abnormalities.¹¹

The first step in the management of status epilepticus is to support vital functions. The airway should be protected, and the patient's vital signs (i.e., through continuous oximetry and electrocardiography) should be closely monitored. Supplemental oxygen at a rate of approximately 4 L per minute is recommended. Intravenous (IV) access should be secured for the administration of parenteral medications, and blood should be drawn for a complete blood count and to measure electrolyte, glucose, calcium, magnesium, and anticonvulsant drug concentrations. A toxicology screen should be performed as well. Medications that can potentiate or precipitate status epilepticus are listed in Table 1 .^3,13

Parenterally administered benzodiazepines, particularly diazepam and lorazepam, are usually the initial drugs used in the treatment of status epilepticus. Seventy-five percent to 90% of the time, these agents diffuse quickly into the CNS and rapidly terminate seizure activity. Both diazepam and lorazepam are equally effective in terminating status epilepticus, but lorazepam has a substantially longer duration of antiseizure effect (12 to 24 hours vs. 15 to 30 minutes). The recommended pediatric IV dose of lorazepam is 0.1 mg/kg (maximum dose, 8 mg) at a rate of 1 to 2 mg per minute. The recommended IV dose of diazepam is 0.2 to 0.5 mg/kg (maximum dose, 10 mg) at a rate of 2 mg per minute. If IV access cannot be obtained, diazepam can also be administered rectally at a dose of 0.5 mg/kg (maximum dose, 20 mg).

Simultaneous loading with phenytoin or fosphenytoin is also recommended. If seizures continue despite these measures, phenobarbital should be administered parenterally. As a last resort, barbiturate coma, high-dose midazolam, high-dose propofol, or general anesthesia with neuromuscular blockade should be employed.¹³

TREATING SEIZURES IN CHILDREN

Determining whether seizure-like symptoms in children constitute a true seizure disorder is important in the management of childhood epilepsy syndromes (see Table 2). Thirty percent of children who have a seizure have a second seizure, and those children who have electroencephalogram (EEG) abnormalities, previous neurologic injury, partial seizures, and/or a family history of seizures are more likely to have additional seizures.^3,13

Once a seizure disorder has been accurately diagnosed, treatment should be started as soon as possible. Both pharmacologic and nonpharmacologic therapies have shown efficacy in treating seizures in children.

Pharmacologic Therapy
Choosing the best medication for a pediatric patient with a seizure depends upon many factors, including patient age, seizure type, general health, concurrent disease states and medication use, and cost.⁷ Clinicians commonly refrain from prescribing antiepileptic medications to previously healthy children with a first afebrile seizure who are not at risk for a second seizure.⁴

Most pediatric seizures are controlled with the first antiepileptic drug that is selected. In order to increase compliance and decrease side effects, antiepileptic drugs should be started at the lowest possible dose and increased slowly. If satisfactory control is not established within the first three to six months, a second antiepileptic drug should be added, with the eventual goal of eliminating the first agent and achieving monotherapy.¹

The antiepileptic medications can be divided into two categories: first- and second-generation drugs. The following section describes the mechanism of action, place in therapy, pediatric dose, and therapeutic range of the first- and second-generation antiepileptic drugs. Side effects and drug interactions associated with these products are listed in Table 3.

First-Generation Antiepileptic Drugs: Phenytoin, phenobarbital, carbamazepine, ethosuximide, and valproic acid are considered first-generation antiepileptic drugs. These products have well-established therapeutic ranges of blood levels but are associated with manyside effects and drug interactions.

Phenytoin--which acts by decreasing the sustained repetitive firing of single neurons by blocking sodium-dependent channels and decreasing depolarization-dependent calcium uptake--is used for primary and secondary generalized tonic-clonic seizures, partial seizures, and status epilepticus.⁴ Pediatric maintenance doses of phenytoin average 5 to 10 mg/kg/day, and a therapeutic range of blood levels of 10 to 20 mg/dL is usually desired. Fosphenytoin, the water-soluble prodrug of phenytoin, is generally preferred over IV phenytoin when immediate loading doses are needed (e.g., status epilepticus).^3,4 Fosphenytoin can be more safely administered via peripheral IV than can phenytoin.⁴

Phenobarbital and primidone, which is metabolized to phenobarbital, act on the gamma-aminobutyric acid (GABA) receptor to increase the chloride channel open duration.^3,14 Phenobarbital is particularly useful for generalized tonic-clonic seizures in children and is dosed at 5 to 10 mg/kg/day. The therapeutic range of phenobarbital is considered to be 15 to 40 mg/dL.^3,4

Carbamazepine, which has a mechanism of action similar to that of phenytoin, is effective for the management of generalized tonic-clonic and partial seizures.³ The drug is usually given orally in doses of 10 to 20 mg/kg/day, and a therapeutic range of blood levels of 8 to 12 mg/dL is commonly desired. Drug metabolism typically increases after the first month of therapy, owing to hepatic autoinduction.⁴

Ethosuximide provides its anticonvulsant action by blocking calcium channels associated with thalamocortical circuitry. This product is considered an effective drug for the management of typical absence epilepsy.³ The typical target pediatric dose is 10 to 20 mg/kg/day, and therapeutic blood levels in the range of 40 to 100 mg/dL are usually desired.⁴

Valproic acid is defined as a broad-spectrum anticonvulsant. It acts by blocking voltage-dependent sodium channels and increasing calcium-dependent potassium conductance. This drug is useful for the management of many seizure types, including generalized tonic-clonic, absence, atypical absence, and myoclonic seizures.³ Valproic acid is available orally and intravenously and is initially dosed at 10 to 20 mg/kg/day; however, doses of 100 mg/kg/day have been documented.¹⁴ When measured, therapeutic blood levels of valproic acid should be in the range of 50 to 100 mg/dL.⁴

Second-Generation Antiepileptic Drugs: Gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide constitute the second-generation antiepileptic drugs. Because these products have very little effect on the cytochrome P-450 enzyme system, they are not associated with as many drug interactions. However, the second-generation products lack established therapeutic ranges of blood levels and are considerably more expensive than the first-generation antiepileptic products.^7,15

Gabapentin exerts its antiepileptic action by binding to neuronal membranes (glutamate synapses) and increasing brain GABA turnover.³ This product is used as an add-on drug for patients with refractory complex partial and secondary generalized tonic-clonic seizures.^3,4,7 Gabapentin is recommended for children 12 years and older.³ The typical target dose of gabapentin is 20 to 40 mg/kg/day, and drug concentrations are not routinely measured.⁴

Lamotrigine affects voltage-sensitive sodium channels and inhibits the presynaptic release of glutamate and aspartate.^3,14 It is primarily used as an add-on drug for the management of complex partial and generalized tonic-clonic seizures in children older than 2 years.^3,7 Doses of lamotrigine range from 5 to 15 mg/kg/day.⁴ Lamotrigine does not require laboratory testing.⁷

Levetiracetam can be used to treat partial onset seizures in children older than 4 years. Doses of levetiracetam begin at 20 mg/kg/day. This drug does not require blood level monitoring.^14,18 The mechanism of action of levetiracetam is unknown.³

Oxcarbazepine, which has a mechanism of action similar to those of phenytoin and carbamazepine, is useful as adjunctive therapy for children with partial seizures.³ This product is usually dosed in the range of 10 to 30 mg/kg/day and does not routinely require laboratory monitoring.⁴ Blood levels are infrequently measured in clinical practice.

Tiagabine inhibits seizure activity by blocking reuptake of the neuroinhibitory transmitter GABA into neuronal and glial cells.³ This drug is effective in the management of complex partial seizures as an add-on drug in children older than 12 years.^3,7 It is most commonly dosed at 1 to 2 mg/kg/day and does not require laboratory testing.⁴

Topiramate produces anticonvulsant action by blocking voltage-dependent sodium channels. This drug is used as adjunctive therapy for refractory complex seizures with or without secondary generalization.³ Topiramate is given to children older than 2 years in doses of 1 to 9 mg/kg/day.^4,7 Blood levels are infrequently measured in clinical practice.

Zonisamide is useful as an adjunctive treatment for partial seizures and may also be useful for myoclonic syndromes in children older than 16 years.³ A dosage of 5 to 10 mg/kg/day is commonly given to children, and blood level monitoring is not required.⁴ The mechanism of action of zonisamide is unclear.

Pediatric Dosing Considerations: Throughout the neonatal period, drug absorption and clearance may change, requiring close monitoring of levels and adjustment of antiepileptic drug dosages. These alterations in pharmacokinetics--as well as changes in metabolic rates, hepatic and renal function, and body mass--continue throughout childhood. More rapid clearance and variability in elimination kinetics of antiepileptic drugs can also affect therapy--children often require higher dosages than those recommended for adults. More frequent dosing may also be needed to avoid low therapeutic blood levels throughout the day. In refractory patients, dosage and therapeutic blood levels should be followed closely. In late childhood and adolescence, therapeutic blood levels tend to remain fairly constant, although adjustments may be required around the time of puberty and during growth spurts.

Nonpharmacologic Therapy
The ketogenic diet--a high-fat, low-carbohydrate, adequate-protein diet--has gained popularity in recent years as a method of managing seizures.^15-17 It has been shown to reduce seizure frequency and to decrease the antiepileptic drug burden and is used primarily to treat children with symptomatic types of epilepsy (e.g., infantile spasms, Lennox-Gastaut syndrome, progressive myoclonic epilepsy). Some data suggest that it may also be effective in the treatment of intractable partial and generalized epilepsy. However, about 10% of patients who practice the ketogenic diet experience side effects, including hypoproteinemia, hemolytic anemia, and kidney stones.¹⁵ Much remains unknown about the ketogenic diet, including its mechanism of action, the optimal protocol, and its full range of applicability.¹⁵

Surgical procedures (e.g., resective surgery, vagus nerve stimulation) are another form of nonpharmacologic therapy used to treat children with seizures. These procedures can be used in pediatric patients who suffer from ongoing seizures or who cannot tolerate antiepileptic drugs; however, because of their associated risks (e.g., stoke, sudden death, infection, vocal cord paralysis), they are used as a last resort.^15,17

REFERENCES

1. McAbee GN, Wark JE. A practical approach to uncomplicated seizures in children. Am Fam Physician. 2000;62:1109-1116.

2. Hirsch E. Childhood epilepsy syndromes with both focal and generalized seizures. Acta Neurol Scand Suppl . 2005;181:52-56.

3. Behrman RE, Kliegman RM, Jenson HB. Nelson Textbook of Pediatrics. 17th ed. Phildelphia, PA: Elsevier Science; 2004.

4. Robertson J, Shilkofski N. The Harriet Lane Handbook. 17th ed. Philadelphia, PA: Elsevier; 2005.

5. Wallace SJ, Farell K. Epilepsy in Children. 2nd ed. London: Arnold; 2004.

6. Hoban TF. Seizure Disorders in Childhood. Loyola University Chicago Stritch School of Medicine Web site. Available at: www.meddean.luc.edu/lumen/MedEd/pedneuro/epilepsy.htm. Accessed March 2006.

7. Flomin O, Nield L, Kamat D. Seizure medications: a review for the primary care pediatrician. Clin Pediatr (Phila). 2005;44:383-391.

8. Spencer DC, Roberts CM. Stopping seizure medications in children: when is it safe? Neurology. 2005;64:E32-E33.

9. Murphy JV, Dehkharghani F. Diagnosis of childhood seizure disorders. Epilepsia. 1994;35 Suppl 2:S7-S17.

10. Pugh MB, Werner B, Filardo TW, et al. Stedman's Medical Dictionary. 27th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2000.

11. Marx JA, Hockberger RS, Walls RM. Rosen's Emergency Medicine: Concepts and Clinical Practice. 5th ed. St Louis, MO: Mosby, Inc; 2002.

12. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med. 2003;349:1257-1266.

13. Rakel RE. Textbook of Family Practice. 6th ed. Phildelphia, PA: W.B. Saunders Company; 2002.

14. Armstrong LL, Goldman MP, Lance L. Drug Information Handbook. 10th ed. Hudson, OH: Lexi Comp, Inc.; 2002.

15. Nadkarni S, LaJoie J, Devinsky O. Current treatments of epilepsy. Neurology. 2005;64:S2-S11.

16. Sinha SR, Kossoff EH. The ketogenic diet. Neurologist. 2005;11:161-170.

17. Faught RE. Management of pediatric epilepsy. Highlights of the American Epilepsy Society 58th Annual Meeting 2005. Available at: www.medscape.com/viewarticle/496930.

18. Shields WD, Koh S. The Role of Newer Antiepileptic Drugs in Children with Epilepsy. Medscape 2000. Available at: www.medscape.com/viewprogram/309?src=search.

To comment on this article, contact [email protected].