Rosalie Sagraves, Pharm.D., FCCP
Spring 1998
Rosalie Sagraves, Pharm.D., FCCP
Spring 1998
Pediatrics
Neurology: The Management of Childhood
Epilepsy and Seizures
Goal: The student should familiarize himself/herslf about pharmacotherapeutic interventions for childhood epilepsy and the management of pediatric seizures.
Learning Objectives:
1. For each of the following seizure types, describe the incidence, etiology, risk factors, clinical signs and symptoms, EEG pattern and pharmacological treatment(s) of choice, if applicable:
Simple partial Complex partial Generalized tonic-clonic Tonic-clonic status epilepticus Absence Atypical absence Myoclonic Atonic/akinetic Febrile convulsions Infantile spasms Neonatal seizures
Please review your class notes from the neurology section.
2. Outline a treatment plan for a patient with any of the above seizure disorders and be able to include:
a. Indication for treatment
b. Drug(s) of choice
c. Rationale for selecting a particular agent(s)
d. Monitoring parameters
e. Adverse effects
f. Doses of antiepileptic agent(s) used for neonatal seizures, infantile spasms, absence seizures, atypical absence seizures, and status epilepticus
3. Discuss recurrence and remission rates for various childhood seizure disorders and factors that influence them.
4. Describe the therapeutic modalities for the treatment of fever in a pediatric patient.
5. List some of the known intellectual and behavior effects associated with the use of phenobarbital in children.
Required Readings:
1. Garnett WR. Status Epilepticus. In: Pharmacotherapy: A pathophysiologic approach, 3rd edition. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells B, Posey LM (eds.). Appleton and Lange, Stamford, CT, 1997:1211-28. Pay particular attention to discussions regarding pediatric patients, especially: Special populations: neonates, infants and children.
2. Garnett WR. Epilepsy. In: Pharmacotherapy: A pathophysiologic approach, 3rd edition. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells B, Posey LM (eds.). Appleton and Lange, Stamford, CT, 1997:1179-1210. Pay particular attention to discussions regarding pediatric patients.
Suggested Readings:
1. Bergman I, Painter MJ, Crumrine PK. Neonatal Seizures. Seminars in Perinatology 1982;6:54-67.
2. Bouma PAD, Peters ACB, Marts ART et al. Discontinuation of antiepileptic therapy: A prospective study in children. Journal of Neurology Neurosurgery Psychiatry 1987;50:1579-83.
3. Consensus Development Conference on Febrile Seizures, National Institutes of Health. Proceedings. Epilepsia 1981;22:377-81.
4. Haines ST, Casto DT. Treatment of infantile spasms. Annals of Pharmacotherapy 1994;28:779-90.
5. Hirtz DG. Generalized tonic-clonic and febrile seizures. Pediatric Clinics of North America 1989;36:365-82.
6. Rosman NP, Colton T, Labazzo J et al. A controlled trial of diazepam administration during febrile illnesses to prevent recurrence of febrile seizures. New England Journal of Medicine 1993;329:79-84.
7. Sinnar S, Vining EPG, Mellits ED et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. New England Journal of Medicine 1985;313:976-80.
I. Classification of Seizures
II. Epidemiology of Epilepsy and Predisposing Factors
A. Incidence: The overall incidence of epilepsy in the general population is estimated to range from 0.5 - 2%. Approximately 80% of all patients with epilepsy have their first seizure before age 20 years. The highest onset of seizures occurring during the first year of life.
B. Age of onset: The incidence and type of epilepsy are related to the age at onset which can differ with the type of seizure disorder.
Figure 1 (Reference 1)
C. Incidence of childhood seizures
Table 1.2-6
Partial Seizures % Generalized Seizures % Simple 1.3- 31.9 Tonic-clonic 7.0 - 27.7 Complex 1.9 - 18.1 Absence 7.4 - 26.8 Secondarily generalized 16.0 - 47.7 Myoclonic 0.4 - 7.4 Others 3.2 - 12.1
D. Age-related factors predisposing to epilepsy1
Table 21
Predisposing Factor Age of Onset of Epilepsy Perinatal injury Birth - age 3 yrs Metabolic defects Birth - age 5 yrs Congenital malformations Birth - age 7 yrs Infection Birth - age 10 yrs Genetic epilepsy Birth - age 20 yrs Postnatal trauma Anytime after birth Brain tumor Adulthood Vascular disease Adulthood
III. Recurrence Rates in Children7,8
A. After a single seizure: 51.8 - 55%
B. After two seizures: 79 - 90%
C. Higher in children with abnormal neurologic examinations at the time of initial seizures
D. Higher in children with histories of partial and/or neonatal seizures
IV. Remission Rates in Children9-13
A. 75 - 80% in children who were gradually withdrawn from anticonvulsants after being seizure free for at least two years while on appropriate anticonvulsant therapy9,10
B. Typically, better prognosis when seizures occur at younger age (excluding children < 2 yrs of age) and have an EEG that showed improvement9-12
C. Children < 2 yrs of age are less likely than older children to have remission from epilepsy after therapy is discontinued and thus may not be good candidates for discontinuing therapy
D. Other factors13
1. Type of seizure(s)
2. Etiology for the seizure disorder
E. AEDs should be withdrawn over 6 weeks or longer13
Table 3. Profiles of Children Who are Candidates for Withdrawal of AEDs
(Reference 13)
Age of Patients Profiles Success Rates <= 15 years of age • One type of seizure • Generalized seizures
• Onset after age 2 years
• No neurological abnormalities
• Normal IQ
• Seizure-free for 2 - 5 years while on AED(s)
75% > 15 years of age • One type of seizure • Generalized seizures
• Onset before age 30 years
• Prompt control of seizures
• Normal EEG with therapy
• Seizure-free for 2 - 5 years while on AED(s)
20%
Table 4. (Reference 1)
Diagnostic Tests for Seizure Disorder
• Medical history
• Physical Examination
• CBC and urinalysis
• Fasting blood sugar (FBS)
• Electrolytes, Ca, Mg, P, BUN
• CT scan
• Lumbar puncture
Table 5. Medical History (Reference 1)
Information obtained from the patient:
• Causes - sound, light, sleep, menses, stopping or decreasing AED
• Aura
• Ictal or postictal experience
• Frequency
Description of the seizure by others:
• First sign
• Pattern of the seizure
• Duration
• After effects
Past events:
• Age at onset of seizures
• Seizures with fever in childhood
• Head trauma (or other event)
• CNS infection
• Family history of epilepsy
Physical signs and symptoms suggesting an underlying cause(s) of epilepsy
Table 6. Differential Diagnosis of Seizures by Age (Reference 1)
| Infants | Children and Adolescents | Adults |
| Breath holding | Benign Paroxysmal vertigo | Drug "blackouts" |
| Hypoglycemia | Drug "blackouts" | Hypoglycemia |
| Syncope | Hypoglycemia | Migraine |
| Tetany | Hysteria | Narcolepsy |
| Migraine | Syncope | |
| Syncope | Transient cerebral vascular insufficiency | |
| Tics |
VII. General Principles of Therapy
The general principles of antiepileptic therapy in pediatric patients are similar to those used in adults. (Refer to the required readings in Pharmacotherapy: A pathophysiologic approach.)
Table 7. Principles of Antiepileptic Drug Therapy (Reference 1)
• Select the appropriate AED for the specific type of epilepsy
• Use one AED until an appropriate therapeutic effect is achieved or toxicity occurs
• Monitor AED(s) serum concentrations
• If seizure control is inadequate with the initial AED, lower the dose to a nontoxic level and add a second AED at a dose to achieve a therapeutic serum concentration
• Do not stop an AED abruptly. This may precipitate seizures or even status epilepticus, especially in a patient who experiences generalized tonic-clonic seizures.
VIII. General Guidelines for Antiepileptic Therapy
(See information on individual antiepileptic agents in section XVII.)
A neonatal seizure does not necessarily represent epileptic activity. It is usually a symptom of an underlying disease process (see etiologies below) and therefore, anticonvulsant therapy is not usually the initial approach to control the seizure.
A. Incidence2
1. 0.15% of term infants
2. = 20% of preterm infants
B. Clinical presentation: Neonatal seizures are usually partial seizures or are subtle because of the neonate's immature cortex. Symptoms may include focal or multifocal clonic seizures, generalized fragmentary clonic movements, focal tonic seizures (includes tonic eye deviations), myoclonic jerks, tonic extension, and subtle signs such as apnea, posturing of a limb, abnormal cry, vasomotor changes; rowing, swimming, or pedaling movements; sudden or repetitive sucking or chewing; and fluttering of the eyelids.
Note: These symptoms may or may not be accompanied by EEG changes. Often it may be difficult to distinguish neonatal seizure activity from normal movements seen in neonates during REM sleep. In addition, a neonatal EEG may be difficult to interpret.
C. Etiologies
Table 8. Etiologies for Neonatal Seizures (Reference 14)
• Trauma and anoxia (e.g., asphyxia, cerebral necrosis, cortical vein thrombosis, intracortical hemorrhage, intraventricular hemorrhage, subdural hematoma)
• Congenital anomalies
• Metabolic problems (e.g., hypocalcemia, hypoglycemia, hypomagnesemia, sodium imbalance)
• Infections (e.g., bacterial meningitis, cerebral abscess, coxsackie meningoencephalitis, cytomegalovirus, herpes encephalitis, syphilis, toxoplasmosis)
• Drug withdrawal (e.g., methadone, heroin, barbiturates, propoxyphene)
• Pyridoxine dependency
• Amino acid disturbances (e.g, maple syrup urine disease, urea cycle abnormalities, nonketotic hyperglycinemia, ketotic hyperglycinemias)
• Kernicterus
• Toxins
• Familial seizures (e.g., phakomatoses, genetic syndromes with mental retardation, benign
familial epilepsy)
D. Neonatal seizure work-up:
1. Must identify the underlying disease or problem
2. Steps:
a. Serum electrolytes and chemistries
b Infectious disease work-up: CBC with platelets, blood culture, urine culture, lumbar puncture with CSF analysis (cell count, protein, glucose) and culture
c. Metabolic disease work-up: serum ammonia, urine amino acids and organic acids
d. Intrauterine infections: TORCH titers (refers to antibody or viral titers that are obtained for toxoplasmosis, other infections such as syphilis, rubella, CMV and coxsackie virus, herpes) for infections associated with congenital neurological abnormalities and seizures.
e. CT scans and MRIs to help identify infarcts, hemorrhages, calcifications or cerebral malformations that may cause seizures
E. Treatment
1. Treatment directed towards correcting the underlying problem. If the underlying problem cannot be identified, then an anticonvulsant may be administered.
2. Length of AED therapy:
a. Once an appropriate AED has been started, doses are adjusted until clinical seizures are controlled or optimal AED serum concentrations have been obtained
b. Usually discontinue AED after one month if neurological examination is normal
c. Usually AED not continued past 3 months unless EEG shows significant, abnormalities that persist or the infant is at high risk for seizure recurrence
Treatment of Neonatal Seizures (Reference 15)
A. Clinical presentation:
Infantile spasms are flexor, extensor, or mixed flexor-extensor spasms of the head, neck, trunk, and/or extremities. Spasms are usually bilateral and symmetric. Flexor spasms may last a few seconds but usually occur in clusters. Spasms are referred to as "Jack-Knife" or "Salaam" spasms and can be mistaken for gastrointestinal disorders such as colic. When spasms begin, they may only be partial seizures such as head nodding.
B. Incidence and age at onset:
1. One case per 2,400 - 6,200 live births
2. Peak age of onset: 2 - 8 months; 85 - 90% of infants having onset within first yr of life
3. Virtually no cases diagnosed after 3 yrs of age
4. 50% seizure free after 3 yrs of age; spasms rarely persist after age 5 yrs
C. Etiology:
1. Metabolic abnormalities (e.g., phenylketonuria)
2. Dysplastic or dysgenetic conditions (e.g., tuberous sclerosis or Sturge-Weber angiomatosis)
3. Prenatal infections (e.g., CMV, syphilis, toxoplasmosis)
4. Perinatally or postnatally acquired encephalopathies (e.g., due to ischemia/hypoxia, hypoglycemia, or infections such as meningitis and encephalitis)
5. Intracranial tumors
6. Idiopathic
D. EEG pattern:2
1. Hypsarrhythmia (high voltage, slow waves and spikes which can be multifocal or polyspikes)
2. May be totally disorganized
E. Prognosis:
1. 87% may have mental retardation or further seizures
2. 35 - 60% develop akinetic, atonic and myoclonic or generalized tonic-clonic seizures usually after 2 yrs of age
3. Approximately 23 - 61% develop Lennox-Gastaut syndrome
4. Prognosis for normal intellectual development is poor despite therapy; 69% of treated patients have severe neurological impairment.
5. Prognosis is dependent on the underlying pathological process and neurological status prior to onset of spasms
6. Prognosis may be better with:
a. Earlier diagnosis and treatment
b. Normal neurological examination before onset of spasms.
c. Onset of spasms after age 4 months
d. The idiopathic type: 30 - 70% chance for normal neurological development Symptomatic type: 5 - 19% chance of normal neurological development
e. Post-immunization cases
F. Treatment
1. Attempt to treat the underlying cause(s)
2. Infantile spasms refractory to conventional AEDs
3. ACTH (adrenocorticotropic hormone, corticotropin) or prednisone is drug of choice. Other AEDs that may be used include clonazepam (in Europe, nitrazepam), valproic acid, and vigabatrin (investigational). (See information on individual AEDs.)
G. ACTH
1. Mechanism for its anticonvulsant activity unknown
2. ACTH and corticosteroids may suppress corticotropin-releasing hormone (CRH)
3. 60 - 70% of children with infantile spasms will respond to ACTH (or corticosteroids), but 30 - 50% relapse. Relapses usually occur within 2 months of stopping therapy.
4. EEG changes usually noted within 2 weeks of therapy, but improvement in EEGs can be seen without clinical improvement and visa versa. EEGs typically worsens with relapse.
5. Dosing:
a. Dosing range: 20 - 40 units/day to 80 - 160 units/day
b. Optimal dose and duration of therapy is controversial
c. Retrospectively, high dose ACTH (40 - 160 units/day) administered IM for 3 to > 12 months has not been shown to be more effective than low dose ACTH (5 - 40 units/day) when given IM for a short time periods (1 - 6 weeks). Possibly response is an all or none phenomenon.
d. A single-blinded, prospective study17 high dose (n = 26) versus low dose ACTH therapy (n = 24) was compared in patients with infantile spasms:
High dose ACTH therapy consisted of 150 units/m2 per day x 3 wks, then 80 units/m2 QOD x 1 wk, then a taper to zero during the next 3 wks.
Low dose ACTH therapy consisted of 20 units/day x 2 wks; then, if a positive response was noted (e.g., cessation of spasms), dose tapered to zero over 1 wk. If no response observed at 2 wks, dose increased to 30 units/day x 4 wks and then tapered to zero over 1 wk.
No significant differences were observed in the response rate, number of responders with normal EEGs post-treatment, or relapse rate between high and low dose groups.
Adverse effects (e.g., irritability, oral thrush, infection, hypokalemia) were similar in both groups, but hypertension more frequent in high dose group (31% vs 4%).
High dose ACTH Low dose ACTH Clinical response 50% 58% Post treatment EEG normalized 23% 21% Relapse rate 15% 21%
e. Typical ACTH dosing regimen:
• Initial dosing of ACTH is 20 to 40 units of gel administered IM once daily for 2 - 4 wks. If the seizures are controlled or decrease, dose is tapered and therapy is continued at lower doses for several wks to months.
• If the child relapses, a second course should be given. Fewer patients, however, respond to a second course.
• If after increasing the dose, if no response seen after 4 wks, ACTH tapered and then discontinued.
• If toxicity occurs before the fourth wk of therapy, ACTH tapered and discontinued.
f. Adverse effects: Cushing syndrome, acneform skin, fluid retention, weight gain, electrolyte disturbances, hypertension, delay in linear growth (height), immune suppression (may lead to an increased risk for infection), ocular opacities, etc. Behavioral changes such as irritability and sleeplessness may occur.
g. ACTH versus prednisone: Appears to be no significant difference in response to ACTH 20 - 30 units/day compared to prednisone 2 mg/kg/day. If a patient fails to respond to one of these agents, they may respond to the other.
H. Other therapeutic agents
1. Benzodiazepines:
a. Clonazepam and nitrazepam
b. Clonazepam may decrease seizure activity without affecting the discharge of the epileptic focus.
c. Abrupt withdrawal of clonazepam may result in seizures and symptoms such as dystonia, irritability, restlessness, tremors, muscle cramps, vomiting and sweating.
2. Valproic acid: Seizure control has been observed in 40 - 70% of patients
3. Vigabatrin (gamma-vinyl GABA): This investigational agent shows promise. Open-labeled trials of vigabatrin for the treatment of infantile spasms have shown seizure control rates of 68 - 73%.
A. Triad of infantile spasms, hypsarrhythmia pattern on EEG, and mental retardation.
B. Treatment: (see information on infantile spasms.)
A. Clinical presentation:
1. Children may have more than one type of seizure (e.g., atypical absence, myoclonic, tonic, tonic-clonic seizures)
2. Incidence of tonic-clonic seizures increase with age
3. Usually mentally retarded
B. Incidence and age at onset:
1. Approximately 3% of all childhood seizures
2. More common in males than females
3. Begins between 1 and 6 yrs of age
C. EEG pattern:2
1. 1.5 - 2.5 Hz diffuse spike-and-wave pattern that may be asymmetrical
2. Other EEG patterns can be observed; depends on the types of seizures that occur
D. Prognosis:18
1. Prognosis is typically poor
2. 80% of patients have seizures as adults
E. Treatment:
1. Therapy individualized depending on the type(s) of seizures present
2. Usually start with monotherapy, but patients may require more than one AED because of mixed seizures
XIII. Typical Absence Seizures
A. Clinical presentation:
1. Brief/ abrupt loss of consciousness for about 20 - 30 seconds; may occur in clusters
2. Patient may stare and be motionless or have distant expression on his/her face
B. Incidence and age at onset:
1. 2 - 11% of all childhood seizures2
2. Average age at onset is 3.8 years; seizures rarely begin before the age of 2 yrs or after teenage years2,18
3. May be a genetic basis associated with the development of absence seizures19
C. Subtypes of typical absence seizures include:
1. Simple, typical absence seizures (brief loss of consciousness)
2. Complex, typical absence seizures (brief loss of consciousness with changes in muscle tone, automatisms or autonomic symptoms)
D. Diagnosis:
1. Clinical presentation (see above)
2. Hyperventilation can be used to induce seizures
3. EEGs are typically 3 Hz spike-and-wave pattern
E. Treatment: AEDs of choice are ethosuximide and valproic acid
XIV. Atypical Absence Seizures
A. Clinical presentation:2,20
1. Seizures longer in duration than typical absence seizures
2. May have changes in muscle tone
B. EEGs may be 1.5 to 2.5 Hz spike-and-wave pattern
C. May be mentally delayed
D. Treatment:
1. Ethosuximide or valproic acid
2. Others: Clonazepam, lorazepam, acetazolamide, and ketogenic diets
Hippocrates (460-377 BC) said that "convulsions occur to children if acute fever be present."
A. Febrile seizures are convulsions that occur without a reason other than fever itself
B. Incidence: 2 - 4% of children > 5 yrs of age will have a febrile seizure. Usually occur between 3 months and 5 yrs of age; most occur at 6 months to 3 yrs of age.
C. Duration: Usually brief and self-limited. Approximately 40% are < 5 minutes in duration, 75 % are < 20 minutes, and only 2 % last > 1 hour.
D. Type: Usually are generalized tonic-clonic; partial seizures occur in 10 - 15% of patients.
E. Simple (benign) vs complex (atypical) febrile seizures: Simple febrile seizures last for < 15 minutes, do NOT have significant focal features, and do NOT occur in multiples within 30 minutes. Complex febrile seizures are usually > than 15 minutes in duration, are focal in nature, and multiple seizures occur within 30 minutes.
F. The fever is usually > 102oF rectally and convulsion is related to the rate of temperature rise.
G. Onset of seizure: A febrile seizure usually occurs early in the course of a febrile illness; usually within the first 24 hrs after the onset of fever.
H. Three risks associated with a febrile seizures:
1. Risk of neurological deficit: Higher risk in children with complex febrile seizures and in those with an early age of onset (< 18 months of age)
2. Risk of recurrence: 25 - 50% of children who experience a febrile seizure will have a recurrence. Risk factors for another febrile seizure occurring include:
a. Young age at onset; children who have first seizure at < 1 yr of age have a 65% chance of recurrence
b. Abnormal neurological status before the first febrile seizure
c. Complex febrile seizure(s)
d. Positive family history of afebrile seizure
3. Risk of epilepsy: Risk is low; however, factors that can increase this risk include:
a. In the low risk group, 2 - 3% of children with a febrile seizure develop epilepsy. These are children who have 0 or 1 of the risk factors listed below. (Although only 2 - 3 % of these children develop epilepsy, this rate is still 2 - 6 times greater than for the general population.)
b. In the high risk group, 13% of children with a febrile seizure develop epilepsy. These children have 2 or more of the following risk factors:
• Family history of nonfebrile seizures
• Abnormal neurologic or developmental status (e.g., mental retardation, cerebral palsy)
• Atypical (complex) febrile seizure
- duration > 15 minutes
- focal seizure
- multiple seizures within 30 minutes
I. Treatment21-23
1. Acute treatment
a. Airway, Breathing and Circulation
b. Control ongoing seizure activity with an IV anticonvulsant (e.g., benzodiazepine such as diazepam)
c. Control the temperature:
1) Remove excess clothing and blankets; decrease room temperature to 26o C to facilitate heat dissipation.
2) Administer an antipyretic such as acetaminophen (10 - 15 mg/kg/dose given every 4 - 6 hrs as needed for fever, not to exceed 5 doses in a 24 hr period)
Aspirin may be used ONLY if the child does NOT have chicken pox, flu or flu-like symptoms, or any viral illness. Aspirin use has been associated with Reye's syndrome when given to children with viral illnesses such as chicken pox or influenza. The dose of aspirin is 10 - 15 mg/kg/dose given every 4 - 6 hours as needed for an elevated temperature.
Ibuprofen 5 - 10 mg/kg/dose given every 6 - 8 hrs may be used to decrease fever (maximum dose 40 mg/kg/day)
3) Tepid sponge baths: After administering an antipyretic, use tepid water to sponge the infant to help decrease the temperature. The antipyretic should be administered before sponging to prolong the effect and avoid shivering.
DO NOT USE ALCOHOL SPONGE BATHS! Toxic effects can occur from the absorption of isopropyl alcohol through a child's skin and by inhalation of the vapors. Alcohol can decrease a child's temperature too rapidly and cause shivering which is the body's way to increase core temperature. This can cause a rebound increase in temperature.
NOTE: Don't forget to provide adequate fluid intake to replace increased insensible water losses due to the increase in a patient's temperature.
d. Treat the underlying cause of fever:
2. Long term prophylaxis of febrile seizures: Long term prophylaxis with phenobarbital reduces the risk of subsequent febrile seizures, but there is no evidence that prophylaxis reduces the risk of nonfebrile seizures (epilepsy).
a. After the first febrile seizure, long term prophylaxis should be considered for the following reasons:23
1) Presence of abnormal neurological development or neurological examination
2) Febrile seizure was complex
3) Positive family history of nonfebrile seizures (epilepsy)
b. Long term prophylaxis may be considered when:
1) The child has multiple febrile seizures
2) The child is < 12 months of age
c. Anticonvulsant prophylaxis is usually continued for 2 yrs after drug initiation or for one yr after the last seizure
NOTE: The above guidelines are from the 1980 NIH consensus statement.23 Since that time, pheno-barbital's adverse effects on learning and cognitive function have been better identified. Because of the high incidence of adverse effects associated with phenobarbital use (see below), many clinicians do not start long term prophylaxis after the first febrile seizure unless the patient has more than one risk factor.24,25
J. Phenobarbital
1. If used for prophylaxis, phenobarbital must be administered daily to maintain therapeutic serum concentrations (> 15 mcg/mL) .
2. Adverse effects occur in up to 40% of patients receiving phenobarbital; 20 - 25% of patients may require discontinuation because of adverse effects that include:23
a. Behavioral changes
• Hyperactivity, irritability; somnolence (rare)
• Begin within the first few months of therapy
• May not be correlated with serum concentrations
• Usually reversible
• Hyperactivity may be seen in febrile seizure patients without phenobarbital treatment
b. Sleep pattern disturbances such as prolonged nocturnal awakenings
c. Interference with higher cortical or cognitive function (e.g., deficits in short-term memory, decreased attention span, defects in general comprehension)
K. Valproic Acid (VPA) is effective in preventing recurrences of febrile seizures. Although behavioral effects are rare and cognitive disturbances in higher cortical function are minimal, other more serious adverse effects of VPA increase the risk of using this agent. Therefore, phenobarbital is considered the drug of choice. VPA is usually reserved for patients who have experienced significant adverse effects to phenobarbital but who require long term prophylaxis.
L. Diazepam: The administration of rectal diazepam suppositories or solution at the time of the febrile illness has been shown to be as effective as daily phenobarbital administration in preventing recurrence of febrile seizures, but rectal dosage forms are not available in the US. Some centers are using injectable diazepam rectally (filtered, if drawn up from an ampule). One study suggests that oral diazepam, if given when the child has a fever, may reduce the risk of recurrent febrile seizures.26
M. Carbamazepine and phenytoin are not effective in preventing the recurrence of febrile seizures.
XVI. Tonic-Clonic Status Epilepticus27
A. Risks
1. Mortality secondary to status epilepticus estimated to be 10 - 12%, some estimates as high as 50% have been reported.
2. Neurologic sequelae after status epilepticus appear proportional to the duration of the episode.
a. Adults: Sequelae rare if status lasts < 1 - 1.5 hrs; patients who died had an average seizure duration of 13 hrs.
b. Children: Minimal duration of status epilepticus leading to brain damage may be as short as 30 minutes.
B. Major precipitating factor of status epilepticus is non-compliance in those with previous seizures. Other common causes include CNS infection, brain tumor, metabolic abnormalities, toxic ingestion, encephalopathy, and head trauma.
C. General management of tonic-clonic status epilepticus:
1. Airway, breathing and circulation
2. Stop the immediate seizure
3. Prevent recurrence
4. Diagnose the underlying cause
D. Drug therapy28
1. Diazepam is the AED of choice, but because of its short duration of action, another anticonvulsant must be given to prevent seizure recurrence. (NOTE: Diazepam is usually not the drug of choice for neonatal status because of benzoic acid and benzyl alcohol content of the IV product; phenobarbital is the preferred drug.)
a. Dose: 0.2 - 0.3 mg/kg administered by slow IV push over 3 - 5 minutes every 15 - 30 minutes or until the seizure stops. Maximum dose is age dependent (see reference 28 for additional information).
b. Adverse effects same as for adults. The combination of IV diazepam followed by IV phenobarbital loading doses in young children may lead to respiratory depression.
c. Route: Usually administered slow IV push. Continuous IV infusion can be used for patients who are refractory to other therapy. Diazepam suppositories and rectal solution are not yet available in the US.
d. Other benzodiazepines: Lorazepam has adverse effects similar to those of diazepam but has a longer duration of seizure control (2 - 4 hrs) compared to diazepam (duration 15 - 30 min). The disadvantage of lorazepam is that it may have a delayed onset (median latency 10 min in children).
2. Phenytoin
a. Place in therapy:
1) Because of rapid penetration into the CNS, phenytoin is the second drug used in status (after diazepam) for older children and adults
2) For children < 6 yrs of age, some pediatricians prefer phenobarbital as the second line agent (after diazepam) and phenytoin as the third line agent
3) Because less sedation is seen after phenytoin loading doses compared to phenobarbital, phenytoin is the preferred agent (in patients of all ages) when the monitoring of neurological status is important (e.g., patients with head trauma, CNS tumor, etc.)
b. Pharmacokinetics
1) Volume of distribution (Vd): Wide range of Vd for phenytoin has been reported for children of different ages.
Age Volume of distribution (Vd) Koren et al. Less than 5 yrs 1.0 to 1.5 L/kg Greater than 8 yrs 0.6 to 0.8 L/kg Average: 0.95+0.35 L/kg Curless et al. <= 1 yr 0.13 to L/kg 2-3 yrs 0.43 L/kg 3-4 yrs 0.96 L/kg 4-5 yrs 0.51 L/kg 6-7 yrs 0.51 L/kg In general: Vd l/kg Premature infants 1.0 to 1.2 Full term 0.8 Infant 0.7 to 0.8 Child 0.7
2) Km, Vmax Estimated daily dose (mg/kg) to attain Cp = 15 Age in years Km mcg/mL Vmax mg/k/day mcg/mL Bauer et al 0.5-3 6.59+4.2 13.95+4.27 9.7* 4-6 6.82+3.5 10.93+3.01 7.5* 7-9 6.51+3.9 10.05+2.64 7.0* 10-16 5.69+2.7 8.25+2.76 6.0* Chiba et al 0.5-3 4.1+5.6 13.8+4.3 10.8** 4-6 4.1+3.6 11.2+3.0 8.8** 7-9 3.6+4.1 9.5+1.5 7.7** 10-16 3.0+2.51 8.0+1.7 6.7** * Values calculated by Bauer et al.
** Calculated values using Km and Vmax derived from study data and Michaelis/Menten equation.
Dose = (Cp(ss) X Km ) / (Vmax + Cp(ss))
c. Doses28
1) Loading doses:
Neonate: 15 - 20 mg/kg
Infants and children: 15 - 18 mg/kg
2) Maintenance:
Age (yrs) mg/kg/day* 0.5 - 3 8 - 10 4 - 6 7.5 - 9 7 - 9 7 - 8 10 - 16 6 - 7
* In divided doses every 12 hours; some children may require daily doses divided into 8 hour intervals
d. Rate of IV administration: As occurs in adults, rapid administration of phenytoin in children may cause hypotension, arrhythmias, etc. Do not infuse phenytoin greater than 1 mg/kg/min or greater than 50 mg/minute to a child.28
3. Phenobarbital28
a. Place in therapy:
1) Phenobarbital is antiepileptic of choice for neonatal status
2) It is usually the third drug of choice for status in older children and adults (after diazepam and phenytoin). Some pediatricians prefer to use phenobarbital after diazepam in children with status who are < 6 yrs of age.
3) Preferred agent (after diazepam) for patients allergic to phenytoin and for patients with cardiac conduction disorders/automaticity (remember phenytoin is a class IB antiarrhythmic agent).
b. Pharmacokinetics
Vd t 1/2 Loading dose Maintenance L/kg Hours mg/kg mg/kg/day Neonates 0.8 45 - 500 20 3 - 4 Infants 0.7 - 0.8 20 - 133 15 - 20 5 - 6 Children 0.6 - 0.7 37 - 73 15 - 20 1 - 5 yrs: 5 - 8 5 - 12 yrs: 4 - 6
> 12 yrs: 1 - 3
c. Rate for IV administration: Do not administer faster than 1 mg/kg/min or faster than 30 mg/minute to a child.28
4. Paraldehyde28
a. Place in therapy: Used to treat status epilepticus refractory to diazepam, phenytoin, and phenobarbital
b. No longer available as a parenteral product in the US. Serious adverse effects (e.g., ardiopulmonary depression, pneumonitis, pulmonary edema, and thrombophlebitis) associated with IV use. Pain, tissue necrosis, nerve damage at injection site, and sterile abscess formation were associated with IM use. Other adverse effects include rash and toxic hepatitis.
c. Rectal administration (as retention enema using oral liquid preparation)
1) Dose: 0.3 mL (300 mg)/kg/dose
2) Dilute paraldehyde 2:1 with mineral oil to avoid corrosion of local mucosa
3) Limitations: rectal absorption during status may be decreased and not be reliable
d. Warnings:
1) Paraldehyde dissolves plastic; a glass syringe should be used to draw up the dose. Rubber tubing may be used for enema administration.
2) Do not use discolored solutions or solutions that smell like vinegar (acetic acid). Paraldehyde decomposes when exposed to light or air to acetaldehyde which then oxidizes to acetic acid. Paraldehyde should be stored in an airtight container and protected from exposure to light.
3) Paraldehyde use contraindicated in hepatic or pulmonary disease
5. Lidocaine is not approved for use in pediatric patients for the treatment of status epilepticus. Furthermore, evidence for proper use and appropriate dosing in children is limited. Lidocaine may be rarely used in children who have seizures that are refractory to other therapy.
6. Although pediatric experience is limited, rectal valproic acid has been used at doses of 20 mg/kg in pediatric patients with status epilepticus.28 The syrup should be diluted 1:1 with water to decrease local irritation when used rectally. Absorption of rectally administered VPA may be delayed and/or decreased during status epilepticus. Because of the limited experience with this therapy, its use should be reserved for children who have seizures that are refractory to other therapy.
7. General anesthesia (with inhalation anesthetics) or barbiturate coma (usually pentobarbital or thiopental) may be required in a child who has seizures refractory to optimal doses of IV diazepam, phenytoin, and phenobarbital (+ paraldehyde).
a. Inhalation anesthetics (e.g., halothane or enflurane) usually in combination with a neuromuscular blocking agent can be used. Neuromuscular blocking agents will stop the outward signs of a seizure by the paralysis of muscular movement; however, the electrical activity of a seizure may continue. EEG monitoring is important to determine if the patient has electrical status which can be harmful and requires treatment even though the patient may not be clinically convulsing.
b. Pentobarbital Coma28,29
1) Loading doses of 10 - 15 mg/kg are given slowly IV over 1 - 2 hrs; hypotension may occur if infused more rapidly
NOTE: Higher loading doses of pentobarbital (15 - 35 mg/kg) are generally NOT recommended because they have been associated with hypotension requiring vasopressor therapy.
2) Maintenance doses: Initial 1 mg/kg/hr; may increase to 2 - 3 mg/kg/hr
3) Monitor RR, HR, BP, EEG, etc.
XVII. Selected antiepileptic agents (comments for
pediatric patients)
A. Carbamazepine28
1. Indications: Drug of first choice for partial seizures, especially complex partial seizures. Also used for generalized seizures (e.g., generalized tonic-clonic seizures). Not effective for absence, myoclonic, or akinetic seizures.
2. Dosing: Because the t1/2 of carbamazepine is shorter in children compared to adults (chronic therapy: 8 - 14 hrs for children vs 12 - 17 hrs for adults), children may require dosing 3 - 4 times per day.
a. Children < 6 yrs: Start with 5 mg/kg/day divided into 1 - 2 doses per day. Increase the dose every 5 - 7 days in 5 mg/kg/day increments. Usual maintenance dose: 20 mg/kg/day in 2 - 4 divided doses.
b. Children 6 - 12 yrs: Start with 10 mg/kg/day in 2 divided doses per day or 100 mg given twice a day. Increase the dose every 5 - 7 days by 100 mg/day increments. Usual maintenance dose: 15 - 30 mg/kg/day in 2 - 4 divided doses. Maximum dose 1000 mg/day.
c. Children > 12 yrs and adults: Start with 200 mg given twice a day. Increase the dose every 5 - 7 days by 200 mg/day increments. Usual maintenance dose: 800 - 1200 mg/day in 3 - 4 divided doses. Some patients require up to 1.6 - 2.4 grams per day.
3. Dose titration: doses started low and titrated upward to decrease adverse CNS effects; titrate to therapeutic serum concentration and seizure control
4. Therapeutic serum concentrations: 4 - 12 mcg/mL. Patients who require higher serum concentrations (8 - 12 mcg/mL) should be closely monitored for CNS side effects.
5. Adverse effects: (See DiPiro).
B. Ethosuximide28
1. Indications: drug of choice for simple absence seizures
2. Dosing:
Initial Dose Maintenance Dose t1/2 Time to mg/kg/day mg/kg/day hrs Steady State (days) Children 15 - 20 15 - 40 30 6 - 7 Adults 15 - 20 15 - 30 50 - 60 10 - 13
a. Usual initial dose: 15 mg/kg/day divided into 2 doses per day (given every 12 hours). Maximum initial dose = 250 mg/dose. (Children > 6 years of age are usually started on 250 mg twice a day.) Daily dose is increased every 4 - 7 days by 125 or 250 mg per day increments with monitoring of serum concentrations and seizure frequency. Dose is titrated upwards to achieve therapeutic serum concentrations with seizure control. Maximum daily dose = 1.5 grams.
b. Therapeutic serum concentration: Cp 40 - 100 mcg/mL
3. Adverse effects: (see DiPiro).
4. Warnings: If ethosuximide is started in patients with both absence and tonic-clonic seizures, an increase in tonic-clonic seizures may occur. Since valproic acid will control both absence and tonic-clonic seizures, it is usually used in these types of patients. If ethosuximide is to be used in patients with both absence and tonic-clonic seizures, phenobarbital or phenytoin should be started first and then after 2-4 wks (i.e., after tonic-clonic antiepileptic agent is therapeutic), ethosuximide is added.
C. Valproic Acid
1. Indications: Effective for absence, partial, myoclonic and generalized seizures. Drug of choice for patients with mixed types of seizures disorders. Effective prophylaxis for febrile seizures but second line agent after phenobarbital. Has been used for infantile spasms.
2. Oral Dosing:28
Initial Dose Maintenance t1/2 Time to mg/kg/day mg/kg/day hrs Steady State (hours) Children 10 - 15 30 - 100 3.5 - 20 20 - 70 Adults 10 - 15 15 - 45 8 - 17 30 - 85 FDA: Maximum = 60
a. Dose titration: Start with 10 - 15 mg/kg/day divided in 1 - 2 doses. Increase dose by 5 - 10 mg/kg/day increments every 3 - 7 days. Usual maintenance for children is 30 - 60 mg/kg/day divided in 2 - 3 doses per day.
1) Higher mg/kg/day doses are required for children vs adults
2) Higher doses (up to 100 mg/kg/day) may be required in children receiving other antiepileptic agents
3) Due to shorter t1/2, a dosing interval of every 6 - 8 hours may be needed in children receiving other antiepileptic agents.
b. Therapeutic serum concentration: 50 - 100 mcg/mL. Some patients may require serum concentrations above 100 mcg/mL (monitor carefully for toxicities).
3. Adverse effects: (see DiPiro)
4. Warnings: Hepatotoxicity is more common in children under 2 yrs of age who are receiving multiple anticonvulsants. These patients may have an increase in a VPA metabolite (4-en-valproic acid) which is potentially hepatotoxic.
D. Felbamate28,30,31(FelbatolTM)
NOTE: Due to its serious adverse effects (i.e., aplastic anemia, hepatic failure), felbamate is NOT a first line antiepileptic agent. Reserved for patients who do not adequately respond to alternative agents and whose epilepsy is so severe that the benefits of the drug outweigh the risk of liver failure or aplastic anemia.
1. Indications:
a. Children > 14 years of age and adults: Monotherapy and adjunctive therapy in the treatment of partial seizures with and without secondary generalization
b. Children > 2 years of age: Adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome
Note: Lennox-Gastaut syndrome accounts for approximately 5% of childhood epilepsies. Characteristics of the syndrome include: onset of multiple seizures during childhood including atonic and atypical absence seizures; slow spike-wave EEG patterns; and mental retardation. Seizures are very difficult to control even with multiple antiepileptic drugs.
2. Dosing: Children with Lennox-Gastaut Syndrome28
a. Dose titration: Felbamate is added at 15 mg/kg/day in divided doses 3 - 4 times per day while reducing antiepileptic drugs by 20% in order to control Cp of concomitant phenytoin, VPA, CBZ and CBZ metabolite. Further reductions of concurrent antiepileptic drug dosage may be needed to minimize adverse effects due to drug interactions. Maximum recommended dose = 3,600 mg/day. (NOTE: Some centers used up to 60 mg/kg/day.)
b. Proposed therapeutic serum concentrations: 30 - 100 mcg/mL.
3. Drug interactions: Felbamate increases phenytoin and VPA serum concentrations and
decreases CBZ serum concentrations while increasing CBZ epoxide (active metabolite) concentrations. Phenytoin and CBZ decrease felbamate concentrations. VPA may possibly
decrease felbamate clearance.
4. Adverse effects (pediatric studies): anorexia, weight loss (10% of body weight), vomiting,
insomnia, headache, somnolence. The dropout rate due to adverse events or intercurrent illnesses in pediatric studies was approximately 6%. These dropouts were due to digestive (1.7%), neurological (1.4%), dermatological (1.4%), psychological (1.1%), and whole body (1%, i.e., fever, fatigue, weight decrease, pain). The most common specific event causing discontinuation of therapy was rash (1.1%). These side effects should resolve as dosage of concomitant antiepileptic drug therapy is decreased.
E. Gabapentin (Neurotin) - please see notes provided by Dr. Fischer
F. Lamotrigine (Lamictal) - please see notes provided by Dr. Fischer
References
1. Clinical Management of Seizures, 2nd edition. Solomon GE, Kutt H, Plum F (eds.). WB Saunders.:Philadelphia 1983.
2. Holmes GL. Diagnosis and management of seizures in children. WB Saunders Co.:Philadelphia 1987.
3. Cavazzuti GB. Epidemiology of different types of epilepsy in school age children of Modena, Italy. Epilepsia 1980;21:57-62.
4. Sofijanov NG. Clinical evolution and prognosis of childhood epilepsies. Epilepsia 1982;23:61-69.
5. Todt H. The late prognosis of epilepsy in childhood: Results of a prospective follow-up study. Epilepsia 1984;25:137-44.
6. Juul-Jensen P. Epilepsy: A clinical and social analysis of 1020 adult patients with epileptic seizures. Acta Neurol Scand 1964;40 (Suppl 5):1-148.
7. Hirtz D, Ellenberg J, Nelson K. The risk of recurrence of non-febrile seizures in children. Neurology 1984;34:637-41.
8. Camfield P, Camfield C, Dooley J et al. Epilepsy after a first unprovoked seizure in childhood. Neurology 1985;35:1657-60.
9. Bouma PAD, Peters ACB, Mars ART et al. Discontinuation of antiepileptic therapy: A prospective study in children. J Neurology Neurosurg Psych 1987;50:1579-83.
10. Shinnar S, Vining EPG, Mellits ED et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. N Engl J Med 1985;313:976-80.
11. Mastropaolo C, Tondi M, Carboni F et al. Prognosis after therapy discontinuation in children with epilepsy. Eur Neurol 1992;32:141-45.
12. Gherpelli JLD, Kok F, dal Forno S et al. Discontinuing medication in epileptic children: A study of risk factors related to recurrence. Epilepsia 1992;33:681-6.
13. Levy RH, Wilensky AJ, Friel PN. Other antiepileptic drugs. In: Evans WE, Schentagg JJ, Justko WJ (eds). Applied pharmacokinetics, 3rd ed. Applied Therapeutics Inc.:Spokane, WA.
14. Bergman I, Painter MJ, Crumrine PK. Neonatal seizures. Seminars in Perinatology 1982;6:54-67.
15. Pedley TA, DeVivo DC. Seizure disorders in infants and children: neonatal seizures. In: Rudolph AM (ed.), Rudolph's Pediatrics 19th edition. Appleton & Lange:Norwalk, CT 1991.
16. Haines ST, Casto DT. Treatment of infantile spasms. Annals of Pharmacotherapy 1994;28:779-90.
17. Hrachovy RA, Frost JD, Glaze DG. High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms. Journal of Pediatrics 1994;124:803-6.
18. Sato S, Dreifuss FE, Penry JK et al. Long-term follow-up of absence seizures. Neurology 1983;33:1590-5.
19. Lockman LA. Absence, myoclonic and atonic seizures. Pediatr Clin North Am 1989;36:331-41.
20. Penry JK. Epilepsy: Diagnosis, management, quality of life. Raven Press:NY 1986.
21. Rosman PN. Febrile seizures. Emergency Med Clin North Am 1987;5:719-37.
22. Garnett WR. Epilepsy (Chapter 51). In: DiPiro JT, Talbert RL, Hayes PE, Yee GC, Matzke LM, Posey LM (eds.). Pharmacotherapy: A pathophysiologic approach. 2nd ed. Elsevier:NY 1992.
23. NIH Consensus statement. Febrile Seizures: Long term management of children with fever-associated seizures. Pediatrics 1980:66:1009-12.
24. Berg AT, Shinnar S, Hauser WA et al. Predictors of recurrent febrile seizures: A metaanalytic review. J Pediatr 1990;116:329-37.
25. Farwell JR, Lee YJ, Hirtz DG et al. Phenobarbital for febrile seizures - effects on intelligence and on seizure recurrence. N Engl J Med 1990;322:364-9.
26. Rosman NP, Colton T, Labazzo J et al. A controlled trial of diazepam administration during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79-84.
27. Garnett WR. Status epilepticus (Chapter 50). In: DiPiro JT, Talbert RL, Hayes PE, Yee GC, Matzke LM, Posey LM (eds.). Pharmacotherapy: A pathophysiologic approach. 2nd ed. Elsevier:NY 1992.
28. Pediatric Dosage Handbook. Taketomo CK, Hodding JH, Kraus DM (eds.). Lexi-Comp:Hudson, OH, 1996.
29. Fischer JH, Raineri DL. Pentobarbital anesthesia for status epilepticus. Clin Pharm 1987;6:601-2.
30. Graves NM. Felbamate. Ann Pharmacother 1993;27:1073-81.
31. The Felbamate Study Group in Lennox-Fastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lenox-Gastaut Syndrome). N Engl J Med 1993;328:29-33.
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