Anti-Epileptic Drugs Used in Pediatric Age
Introduction to Antiepileptic Drugs in Pediatrics
Antiepileptic drugs (AEDs) play a crucial role in managing pediatric epilepsy. The goal of AED therapy is to achieve seizure freedom without significant side effects, allowing for normal growth and development. Choosing the appropriate AED depends on various factors, including:
- Seizure type and epilepsy syndrome
- Age of the child
- Comorbidities
- Potential drug interactions
- Side effect profile
- Ease of administration
It's essential to start with a single AED (monotherapy) at a low dose and gradually titrate to the lowest effective dose. If monotherapy fails, consider alternative monotherapy or rational polytherapy.
Classification and Mechanism of Action
AEDs can be broadly classified based on their primary mechanism of action:
- Sodium channel blockers: Reduce neuronal excitability by blocking voltage-gated sodium channels (e.g., carbamazepine, phenytoin, lamotrigine)
- GABA enhancers: Increase inhibitory neurotransmission (e.g., benzodiazepines, barbiturates, vigabatrin)
- Calcium channel modulators: Reduce neurotransmitter release (e.g., ethosuximide, gabapentin)
- Glutamate antagonists: Decrease excitatory neurotransmission (e.g., topiramate, perampanel)
- SV2A modulators: Modify synaptic vesicle function (e.g., levetiracetam, brivaracetam)
- Multiple mechanisms: Some AEDs act through various mechanisms (e.g., valproic acid, topiramate)
Common Antiepileptic Drugs in Pediatrics
- Carbamazepine (CBZ): Effective for focal seizures and generalized tonic-clonic seizures. Not recommended for absence or myoclonic seizures.
- Valproic acid (VPA): Broad-spectrum AED effective for most seizure types. First-line for generalized epilepsies. Use with caution in young children due to hepatotoxicity risk.
- Levetiracetam (LEV): Broad-spectrum AED with a favorable side effect profile. Useful for both focal and generalized seizures.
- Oxcarbazepine (OXC): Similar to carbamazepine but with a better side effect profile. Effective for focal seizures.
- Lamotrigine (LTG): Broad-spectrum AED effective for both focal and generalized seizures. Requires slow titration due to risk of rash.
- Topiramate (TPM): Broad-spectrum AED with multiple mechanisms of action. Effective for various seizure types but may cause cognitive side effects.
- Ethosuximide (ETX): First-line treatment for childhood absence epilepsy.
- Phenobarbital (PB): Commonly used in neonatal seizures but associated with cognitive side effects in long-term use.
- Clobazam (CLB): Benzodiazepine effective as adjunctive therapy for Lennox-Gastaut syndrome and refractory focal seizures.
Dosage and Administration
Dosing of AEDs in pediatrics is weight-based and may require frequent adjustments as the child grows. Always consult current guidelines and package inserts for specific dosing information. General principles include:
- Start with a low dose and gradually titrate to the lowest effective dose
- Divide daily doses to minimize peak-related side effects
- Consider extended-release formulations to improve compliance
- Adjust dosage based on clinical response and serum levels (for drugs with established therapeutic ranges)
Example dosing ranges (for reference only, always verify):
- Carbamazepine: 10-20 mg/kg/day divided BID-TID
- Valproic acid: 15-60 mg/kg/day divided BID-TID
- Levetiracetam: 20-60 mg/kg/day divided BID
- Oxcarbazepine: 10-30 mg/kg/day divided BID
- Lamotrigine: 1-15 mg/kg/day (depends on concurrent AEDs)
Side Effects and Monitoring
Common side effects of AEDs in pediatrics include:
- Drowsiness, dizziness, and fatigue
- Behavioral changes (irritability, hyperactivity)
- Cognitive impairment (attention, memory)
- Gastrointestinal disturbances
- Rash (particularly with lamotrigine, carbamazepine)
- Weight changes (gain with valproate, loss with topiramate)
Monitoring recommendations:
- Baseline: Complete blood count, liver function tests, renal function
- Regular follow-up: Clinical assessment, growth parameters, developmental milestones
- Drug levels: For AEDs with established therapeutic ranges (e.g., carbamazepine, valproic acid, phenytoin)
- Specific monitoring:
- Valproic acid: Liver function, platelets, ammonia levels
- Carbamazepine: Sodium levels, CBC
- Phenytoin: Folate levels, vitamin D
Special Considerations in Pediatrics
- Age-specific pharmacokinetics: Children may metabolize AEDs differently than adults, often requiring more frequent dosing or higher mg/kg doses.
- Impact on development: Consider potential effects on cognitive and physical development when choosing AEDs.
- Formulations: Availability of liquid formulations or sprinkle capsules can improve adherence in young children.
- Drug interactions: Be aware of interactions with other medications commonly used in pediatrics (e.g., antibiotics, antihistamines).
- Teratogenicity: Important consideration for adolescent females of childbearing potential.
- Discontinuation: Carefully weigh risks and benefits before discontinuing AEDs in seizure-free children. Typically consider after 2 years of seizure freedom.
- Ketogenic diet: May be used as an adjunctive therapy in refractory epilepsy, requiring adjustment of AED doses.
Carbamazepine (CBZ)
Chemistry
Carbamazepine is a dibenzazepine derivative. Its chemical structure is 5H-dibenzo[b,f]azepine-5-carboxamide.
Mechanism of Action
Primarily acts by blocking voltage-gated sodium channels, reducing neuronal excitability. It also affects other neurotransmitter systems, including GABA and glutamate.
Indications
- Focal seizures (with or without secondary generalization)
- Generalized tonic-clonic seizures
- Mixed seizure disorders
Contraindications
- History of bone marrow depression
- Known hypersensitivity to carbamazepine or tricyclic compounds
- Concomitant use with MAO inhibitors
- Atrioventricular heart block
Adverse Effects
- Common: Dizziness, drowsiness, ataxia, nausea
- Dermatologic: Rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis)
- Hematologic: Aplastic anemia, agranulocytosis (rare but serious)
- Endocrine: Hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH)
- Hepatic: Elevated liver enzymes, rarely hepatotoxicity
Special Points
- Autoinduction: CBZ induces its own metabolism, often requiring dose adjustments
- Strong inducer of CYP3A4, affecting metabolism of many other drugs
- Therapeutic drug monitoring is recommended (target range: 4-12 µg/mL)
- HLA-B*1502 testing recommended in patients of Asian ancestry due to increased risk of Stevens-Johnson syndrome
- Extended-release formulations can improve adherence and reduce peak-related side effects
Valproic Acid (VPA)
Chemistry
Valproic acid is a branched short-chain fatty acid. Its chemical name is 2-propylpentanoic acid.
Mechanism of Action
Multiple mechanisms, including enhancement of GABA-ergic neurotransmission, inhibition of voltage-gated sodium channels, and modulation of T-type calcium channels.
Indications
- Broad-spectrum antiepileptic drug
- Generalized seizures (absence, tonic-clonic, myoclonic)
- Focal seizures
- First-line for many generalized epilepsy syndromes
Contraindications
- Known or suspected mitochondrial disorders
- Urea cycle disorders
- Severe liver disease or significant hepatic dysfunction
- Porphyria
Adverse Effects
- Gastrointestinal: Nausea, vomiting, dyspepsia
- Neurological: Tremor, sedation, ataxia
- Metabolic: Weight gain, hyperammonemia
- Hepatic: Hepatotoxicity (rare but potentially fatal, higher risk in young children)
- Hematologic: Thrombocytopenia, platelet dysfunction
- Endocrine: Polycystic ovary syndrome, hypothyroidism
- Teratogenic effects (neural tube defects, cognitive impairment)
Special Points
- High risk of hepatotoxicity in children under 2 years, especially with polytherapy or inborn errors of metabolism
- Regular monitoring of liver function, complete blood count, and ammonia levels recommended
- Therapeutic drug monitoring advised (target range: 50-100 µg/mL)
- Consider carnitine supplementation, especially in high-risk patients
- Avoid in female adolescents of childbearing potential if possible due to teratogenicity and risk of polycystic ovary syndrome
Levetiracetam (LEV)
Chemistry
Levetiracetam is a pyrrolidone derivative. Its chemical name is (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide.
Mechanism of Action
Binds to the synaptic vesicle protein SV2A, modulating neurotransmitter release. The exact mechanism of its antiepileptic effect is not fully understood.
Indications
- Focal seizures
- Generalized tonic-clonic seizures
- Myoclonic seizures in juvenile myoclonic epilepsy
- Adjunctive therapy in many pediatric epilepsy syndromes
Contraindications
- Hypersensitivity to levetiracetam or other pyrrolidone derivatives
Adverse Effects
- Behavioral: Irritability, aggression, mood changes
- Neurological: Somnolence, dizziness, headache
- Gastrointestinal: Nausea, vomiting
- Rare: Psychosis, suicidal ideation
Special Points
- Favorable pharmacokinetic profile with minimal drug interactions
- Available in intravenous formulation for acute seizure management
- No routine blood monitoring required
- Dose adjustment needed in renal impairment
- Behavioral side effects may be more pronounced in children with preexisting behavioral issues
- Considered relatively safe during pregnancy (Category C)
Oxcarbazepine (OXC)
Chemistry
Oxcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon-carbon double bond on the dibenzazepine ring.
Mechanism of Action
Primarily blocks voltage-sensitive sodium channels. Its active metabolite, monohydroxy derivative (MHD), is largely responsible for the pharmacological effect.
Indications
- Focal seizures (monotherapy or adjunctive therapy)
- Generalized tonic-clonic seizures (secondary generalization)
Contraindications
- Known hypersensitivity to oxcarbazepine or eslicarbazepine
Adverse Effects
- Neurological: Dizziness, somnolence, headache, ataxia
- Gastrointestinal: Nausea, vomiting, abdominal pain
- Metabolic: Hyponatremia (more common than with carbamazepine)
- Dermatological: Rash (including rare cases of Stevens-Johnson syndrome)
Special Points
- Better tolerability profile compared to carbamazepine
- Lower risk of hepatic enzyme induction compared to carbamazepine
- Monitor sodium levels, especially at initiation and dose increases
- Cross-reactivity with carbamazepine hypersensitivity in about 25-30% of patients
- Potential for decreased efficacy of oral contraceptives
- May be used in patients who have previously experienced mild sensitivity to carbamazepine
Lamotrigine (LTG)
Chemistry
Lamotrigine is a phenyltriazine derivative. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.
Mechanism of Action
Primarily acts by blocking voltage-sensitive sodium channels. It also inhibits the release of excitatory neurotransmitters, particularly glutamate.
Indications
- Focal seizures
- Generalized seizures (including absence seizures)
- Lennox-Gastaut syndrome
- Dravet syndrome (as adjunctive therapy)
Contraindications
- Known hypersensitivity to lamotrigine
Adverse Effects
- Dermatological: Rash (including serious reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis)
- Neurological: Dizziness, ataxia, somnolence, headache
- Gastrointestinal: Nausea, vomiting
- Psychiatric: Insomnia, irritability
Special Points
- Requires slow titration to minimize risk of rash
- Titration schedule depends on concomitant medications (especially valproic acid)
- Lower risk of cognitive side effects compared to many other AEDs
- May have mood-stabilizing properties
- No routine blood monitoring required
- Generally weight-neutral
- Considered one of the safer AEDs in pregnancy (Category C)
Topiramate (TPM)
Chemistry
Topiramate is a sulfamate-substituted monosaccharide. Its chemical name is 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate.
Mechanism of Action
Multiple mechanisms, including blockade of voltage-dependent sodium channels, enhancement of GABA-A receptor activity, antagonism of AMPA/kainate glutamate receptors, and inhibition of carbonic anhydrase.
Indications
- Focal seizures
- Generalized tonic-clonic seizures
- Lennox-Gastaut syndrome
- Adjunctive therapy in Dravet syndrome
Contraindications
- Hypersensitivity to topiramate or its components
Adverse Effects
- Cognitive: Word-finding difficulties, confusion, memory impairment
- Neurological: Paresthesias, somnolence, dizziness
- Metabolic: Weight loss, metabolic acidosis
- Ophthalmological: Acute myopia and secondary angle closure glaucoma
- Renal: Increased risk of kidney stones
Special Points
- Cognitive side effects may be more pronounced in children and may affect learning
- Monitor for metabolic acidosis, especially in younger children
- Advise increased fluid intake to reduce risk of kidney stones
- May decrease efficacy of oral contraceptives
- Carbonic anhydrase inhibition may alter the taste of carbonated beverages
- Potential benefit in migraine prophylaxis
- Teratogenic potential (oral clefts) - use with caution in women of childbearing age
Ethosuximide (ETX)
Chemistry
Ethosuximide is a succinimide derivative. Its chemical name is 3-ethyl-3-methylpyrrolidine-2,5-dione.
Mechanism of Action
Primarily works by reducing low-threshold calcium currents in thalamic neurons, specifically T-type calcium channels.
Indications
- First-line treatment for absence seizures (petit mal)
- May be effective in some cases of atypical absence or myoclonic seizures
Contraindications
- Hypersensitivity to ethosuximide or other succinimides
Adverse Effects
- Gastrointestinal: Nausea, vomiting, abdominal pain, anorexia
- Neurological: Drowsiness, dizziness, headache, ataxia
- Psychiatric: Behavioral changes, including aggression or psychosis (rare)
- Hematologic: Rare cases of aplastic anemia and agranulocytosis
Special Points
- High efficacy for absence seizures (around 70% become seizure-free)
- Minimal drug interactions compared to many other AEDs
- Available as a syrup, which can improve adherence in young children
- Therapeutic drug monitoring may be helpful (target range: 40-100 µg/mL)
- Periodic blood counts recommended due to rare hematologic effects
- Generally does not affect cognition or learning
Phenobarbital (PB)
Chemistry
Phenobarbital is a barbituric acid derivative. Its chemical name is 5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione.
Mechanism of Action
Enhances GABA-mediated inhibition by prolonging the opening of GABA-A receptor chloride channels. It also reduces glutamate-mediated excitation.
Indications
- Neonatal seizures
- Status epilepticus
- Focal and generalized seizures (less commonly used due to side effects)
Contraindications
- Acute intermittent porphyria
- Severe respiratory depression
- Hypersensitivity to barbiturates
Adverse Effects
- Cognitive: Sedation, cognitive impairment, learning difficulties
- Behavioral: Hyperactivity, irritability (particularly in children)
- Dermatologic: Rare severe cutaneous reactions (Stevens-Johnson syndrome)
- Metabolic: Vitamin D deficiency, osteomalacia with long-term use
- Dependency and withdrawal syndrome with abrupt discontinuation
Special Points
- Long half-life allows for once-daily dosing
- Potent inducer of hepatic enzymes, leading to numerous drug interactions
- Therapeutic drug monitoring recommended (target range: 15-40 µg/mL)
- Still widely used in resource-limited settings due to low cost
- Use in children is limited due to cognitive and behavioral side effects
- May cause folic acid deficiency; supplementation may be necessary
Clobazam (CLB)
Chemistry
Clobazam is a 1,5-benzodiazepine. Its chemical name is 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione.
Mechanism of Action
Enhances GABA-mediated inhibition by binding to GABA-A receptors, specifically at a site distinct from the binding site of other benzodiazepines.
Indications
- Adjunctive treatment of Lennox-Gastaut syndrome
- Refractory focal seizures
- Dravet syndrome
Contraindications
- Hypersensitivity to clobazam or other benzodiazepines
Adverse Effects
- Neurological: Somnolence, sedation, ataxia
- Behavioral: Irritability, aggression
- Respiratory: Increased risk of respiratory depression, especially when combined with other CNS depressants
- Potential for tolerance and dependence
Special Points
- May be more effective and better tolerated than other benzodiazepines for long-term use in epilepsy
- Available in tablet and oral suspension forms
- Metabolism affected by CYP2C19 inhibitors and inducers
- Lower abuse potential compared to other benzodiazepines
- Monitor for signs of tolerance and consider periodic attempts at dose reduction
Zonisamide (ZNS)
Chemistry
Zonisamide is a sulfonamide derivative. Its chemical name is 1,2-benzisoxazole-3-methanesulfonamide.
Mechanism of Action
Multiple mechanisms including blockade of voltage-dependent sodium and T-type calcium channels, modulation of GABAergic and dopaminergic neurotransmission, and weak inhibition of carbonic anhydrase.
Indications
- Focal seizures
- Generalized seizures
- Adjunctive therapy in Lennox-Gastaut syndrome and infantile spasms
Contraindications
- Hypersensitivity to zonisamide or sulfonamides
Adverse Effects
- Neurological: Somnolence, dizziness, ataxia, cognitive slowing
- Psychiatric: Irritability, depression, psychosis (rare)
- Metabolic: Weight loss, metabolic acidosis
- Dermatologic: Rash (including Stevens-Johnson syndrome, rarely)
- Renal: Increased risk of kidney stones
Special Points
- Long half-life allows for once-daily dosing
- Monitor for metabolic acidosis, especially in younger children
- Advise increased fluid intake to reduce risk of kidney stones
- May cause oligohidrosis (decreased sweating), increasing risk of hyperthermia in children
- Potential benefit in migraine prophylaxis
- Teratogenic potential - use with caution in women of childbearing age
Anti-Epileptic Drugs Used in Pediatric Age
- Question: Which anti-epileptic drug is commonly used as first-line treatment for absence seizures in children? Answer: Ethosuximide
- Question: What is the mechanism of action of valproic acid? Answer: Increases GABA levels and blocks sodium channels
- Question: Which anti-epileptic drug is associated with severe hepatotoxicity, particularly in children under 2 years old? Answer: Valproic acid
- Question: What is the primary indication for using carbamazepine in pediatric epilepsy? Answer: Focal seizures
- Question: Which anti-epileptic drug is particularly effective for Lennox-Gastaut syndrome? Answer: Rufinamide
- Question: What is the mechanism of action of levetiracetam? Answer: Binds to synaptic vesicle protein SV2A
- Question: Which anti-epileptic drug is often used as first-line treatment for infantile spasms? Answer: Vigabatrin
- Question: What is the most common side effect of topiramate in children? Answer: Cognitive slowing
- Question: Which anti-epileptic drug can cause a blue discoloration of the skin? Answer: Oxcarbazepine
- Question: What is the mechanism of action of lamotrigine? Answer: Blocks voltage-sensitive sodium channels
- Question: Which anti-epileptic drug is associated with a high risk of Stevens-Johnson syndrome? Answer: Lamotrigine
- Question: What is the primary indication for using ethosuximide in pediatric epilepsy? Answer: Absence seizures
- Question: Which anti-epileptic drug is known to cause weight loss in children? Answer: Topiramate
- Question: What is the mechanism of action of phenobarbital? Answer: Enhances GABA-mediated inhibition
- Question: Which anti-epileptic drug is often used as a second-line treatment for status epilepticus in children? Answer: Phenytoin
- Question: What is the most common side effect of valproic acid in children? Answer: Weight gain
- Question: Which anti-epileptic drug can cause hyperammonemia in children? Answer: Valproic acid
- Question: What is the mechanism of action of gabapentin? Answer: Binds to the α2δ subunit of voltage-gated calcium channels
- Question: Which anti-epileptic drug is particularly effective for Dravet syndrome? Answer: Stiripentol
- Question: What is the primary indication for using clobazam in pediatric epilepsy? Answer: Lennox-Gastaut syndrome
- Question: Which anti-epileptic drug can cause aplastic anemia as a rare but serious side effect? Answer: Carbamazepine
- Question: What is the mechanism of action of vigabatrin? Answer: Irreversibly inhibits GABA transaminase
- Question: Which anti-epileptic drug requires regular monitoring of visual fields in children? Answer: Vigabatrin
- Question: What is the primary indication for using zonisamide in pediatric epilepsy? Answer: Broad-spectrum anti-epileptic for various seizure types
- Question: Which anti-epileptic drug can cause gingival hyperplasia in children? Answer: Phenytoin
- Question: What is the mechanism of action of oxcarbazepine? Answer: Blocks voltage-sensitive sodium channels
- Question: Which anti-epileptic drug is often used as add-on therapy for Lennox-Gastaut syndrome? Answer: Felbamate
- Question: What is the most common side effect of levetiracetam in children? Answer: Behavioral changes (irritability, aggression)
- Question: Which anti-epileptic drug requires regular monitoring of liver function in children? Answer: Valproic acid
- Question: What is the mechanism of action of perampanel? Answer: AMPA receptor antagonist
External Resources
- International League Against Epilepsy: Guidelines for Treatment
- American Epilepsy Society: Clinical Practice Guidelines
- StatPearls: Pediatric Seizure Medications
- American Academy of Pediatrics: Managing Epilepsy and Seizures
- EMA Guideline on Clinical Investigation of Medicinal Products in the Treatment of Epileptic Disorders
- Review: Antiepileptic Drugs in Pediatrics
