Epilepsy%20(pediatric) Treatment
Principles of Therapy
In most clinical settings, seizures are not treated unless ≥2 unprovoked seizures are demonstrated within a 6-month period
Patient Experiences a Single Seizure
- Detailed history needs to be taken to rule out any previous absence, myoclonic, or partial seizures because patients with undiagnosed epilepsy may present with a single generalized tonic-clonic seizure
Decision to Treat Single Seizure
- Whether or not to treat a single seizure will be based upon the estimates of risk recurrence which vary
- Highest recurrence risk rates (up to 90%) are seen in patients who demonstrate epileptic discharges on EEG or have congenital neurological deficits
- Lowest recurrence risk rates (13-40%) are in patients who experience acute symptomatic seizures (provoked) or those with a normal EEG and no identifiable cause for seizure
- Treatment with anticonvulsants can reduce the risk of recurrence by half
- Early treatment has not shown to alter the prognosis of epilepsy
- Consultation with epilepsy specialist will be needed to decide whether or not to treat a single seizure
Single Generalized Tonic-Clonic Seizure
- Patient could be given anticonvulsant therapy if:
- History of previous myoclonic, absence or focal seizures
- EEG shows unquestionable epileptic discharges
- Structural abnormalities are present in brain imaging
- Patient has congenital neurological deficit
- Patient decides the risk of recurrence is not acceptable
Pharmacological Therapy
- Treatment initiation using a single antiepileptic drug is recommended
- Shifting to another monotherapy may be done if initial treatment is unsuccessful
- If with continued treatment failure, may add a 2nd drug and gradually increase to maximum tolerated dose while simultaneously tapering dose of 1st drug
- Combination therapy may be considered if removal of the initial or 2nd drug is still ineffective
- Consider combination therapy if patient has substantial seizure control with 1st-line agent but still experiences seizures at maximum dose
- If various combinations fail to confer seizure freedom, return to the combination with the best control of seizures and best tolerability
- Drugs used in combination should be matched to patient’s seizure type
- Maximum 3 drugs can be combined; better if only 2 are used
- Combined antiepileptic drugs should have different mechanisms of action
Pharmacotherapy
Anticonvulsants (1st-Line Anticonvulsants)
Choice of anticonvulsant drugs will be based on their indications, adverse effects and interaction profiles
Carbamazepine
- Used in male patients with self-limited epilepsy with autonomic seizures (SeLEAS) and childhood occipital visual epilepsy (COVE)
- Used as 2nd-line monotherapy option or as 1st-line add-on treatment option in patients with focal seizures and self-limited epilepsy with centrotemporal spikes (SeLECTS)
- Also used as adjunctive treatment for refractory focal seizures, SeLEAS, and COVE
- Should be avoided in absence, myoclonic, tonic and atonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, SeLECTS, and epilepsy with myoclonic-atonic seizures (Doose syndrome)
- Classification: Dibenzazepine derivative
Ethosuximide
- Used as first-line therapy to treat absence seizures
- Also used in childhood or juvenile absence epilepsy in combination with Lamotrigine or Valproate if unresponsive to 2 1st-line antiepileptic drugs
- Use of Valproate for girls with childbearing potential should be avoided
- Used as 3rd-line or add-on treatment option in patients with epilepsy with myoclonic-atonic seizures (Doose syndrome)
- Classification: Succinimide compound
Lamotrigine
- Used as 1st-line therapy for focal seizures, generalized tonic-clonic seizures, absence seizures with other seizure types, tonic or atonic seizures, SeLECTS, SeLEAS, and COVE
- Treatment option for patients with absence seizures unresponsive to Ethosuximide or Valproate
- Off-label use as 1st-line therapy in patients with focal seizures, SeLECTS, and tonic or atonic seizures aged <13 years old, or in patients <2 years old with focal seizures or tonic or atonic seizures if used as 1st-line add-on treatment
- Used as a 1st-line therapy or 2nd-line treatment option to Valproate for idiopathic generalized onset epilepsy, tonic or atonic seizures, and generalized tonic-clonic seizures, but used off-label in patients <13 years of age and in patients <2 years old if used as add-on treatment
- Used as 3rd-line monotherapy or add-on treatment in absence seizures, or as 2nd-line monotherapy or add-on treatment in absence seizure with other seizure types, and myoclonic seizures
- Off-label use in patients <2 years old if used as 2nd-line monotherapy or add-on treatment
- Also used as adjunctive treatment for refractory focal seizures, generalized tonic-clonic seizures, generalized tonic or atonic seizure, Lennox-Gastaut syndrome, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, SeLEAS, and COVE, and as tertiary therapy for myoclonic seizures
- Off-label use in patients with myoclonic seizures, tonic or atonic seizures, idiopathic generalized onset epilepsy, or Lennox-Gastaut syndrome <13 years old if used as 2nd-line monotherapy or <2 years of age if used as add-on treatment
- Should be avoided in patients with Dravet syndrome, Lennox-Gastaut syndrome, and SeLECTS
- Classification: Phenyltriazine compound
Levetiracetam
- Used as 1st-line therapy option for focal seizures, juvenile myoclonic epilepsy, and SeLECTS
- Used off-label as a 1st-line therapy or 2nd-line treatment option to Valproate in patients <12 years old if used as add-on treatment
- Used off-label in patients with focal seizures and SeLECTS <16 years of age, or <4 years old if used as 1st-line add-on treatment
- Also recommended as 2nd-line therapy for patients with SeLEAS and COVE if treatment failure with Carbamazepine or Lamotrigine occurs
- Also used as adjunctive treatment for refractory focal seizures, primary generalized tonic-clonic seizures,myoclonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, infantile spasms, SeLEAS, and COVE, and tertiary and adjunctive therapy for absence seizures
- Classification: Analogue of Piracetam which is a nootropic
Oxcarbazepine
- Used as alternative 1st-line monotherapy for SeLEAS and COVE
- Used as 2nd-line therapy option in patients with focal seizures and SeLECTS, and used as off-label for patients <6 years old, or <6 years old if used as 1st-line add-on treatment
- Recommended as adjunctive treatment for patients with refractory focal seizures, SeLEAS, and COVE
- At 2400 mg/day, was shown to be effective in monotherapy for refractory focal epilepsy
- Similar efficacy to Carbamazepine
- Additional benefits were seen when Oxcarbazepine was added to Carbamazepine therapy
- Better tolerated than Carbamazepine, fewer drug interactions and less physician monitoring is required
- Should be avoided in absence, tonic or atonic seizures, Dravet syndrome, Lennox-Gastaut syndrome, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, myoclonic seizures, SeLECTS, and epilepsy with myoclonic-atonic seizures (Doose syndrome)
- Classification: 10-keto analogue of Carbamazepine
Topiramate
- Used as 1st-line monotherapy in patients with newly diagnosed patients with epilepsy, or conversion to monotherapy, or as adjunctive treatment for newly diagnosed or refractory focal seizure, generalized tonic-clonic seizures, tonic or atonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, SeLECTS, SeLEAS, and COVE
- Also used as tertiary treatment for patients with tonic or atonic seizures or Lennox-Gastaut syndrome
- In some countries, Topiramate is only approved as adjunctive treatment
- Used off-label in patients <2 years old with generalized tonic-clonic seizures, and in refractory focal seizures if used as 1st-line add-on treatment, and in Lennox-Gastaut syndrome
- Used as 2nd-/3rd-line monotherapy in tonic or atonic seizures, and idiopathic generalized epilepsy
- Off-label use in patients with tonic or atonic seizures <6 years old as monotherapy, and in <2 years old if used as add-on treatment
- Classification: Sulfamate-substituted monosaccharide
Valproate (Divalproex, Sodium valproate, Valproic acid)
- Used as 1st-line therapy to treat newly diagnosed focal seizures, generalized tonic-clonic seizures, absence seizures with other seizure types, myoclonic seizures, tonic or atonic seizures, all generalized seizures, idiopathic generalized epilepsy, and epilepsy with myoclonic-atonic seizures (Doose syndrome)
- May also be used as 1st-line therapy for juvenile myoclonic epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, SeLEAS, and COVE
- Used as 2nd-line monotherapy or add-on treatment in absence seizures and infantile spasms
- Also recommended as 2nd-line IV therapy for patients with convulsive status epilepticus if unresponsive to 2 doses of benzodiazepine
- Also used as adjunctive treatment for refractory focal seizures, generalized tonic-clonic seizures, absence seizures, juvenile myoclonic epilepsy, infantile spasms, SeLEAS, and COVE
- The use of Valproic acid in combination with Lamotrigine or Ethosuximide for childhood absence epilepsy maybe considered for patients unresponsive to 2 1st-line antiepileptic drugs
- Use of Valproate for girls with childbearing potential should be avoided
- Important adverse effect is weight gain
- Classification: Carboxylic acid derivative
Anticonvulsants (Adjunctive/Tertiary Anticonvulsants)
- Recommended for patients who have not benefited from treatment with 1st-line antiepileptic medications or for whom these drugs are not suitable (eg poor tolerance, contraindications to 1st-line drugs, etc)
Brivaracetam
- Used as 2nd-line monotherapy or adjunctive therapy for focal onset seizures in patients ≥4 years old as oral therapy, for patients ≥16 years old as both oral and intravenous therapy, generalized tonic-clonic seizures, and myoclonic seizures
- Used as off-label in patients with focal seizures <4 years of age
- Classification: 2-pyrrolidine derivative and Levetiracetam analog
Eslicarbazepine acetate
- Used as tertiary treatment for refractory focal seizure, SeLEAS, and COVE if adjunctive therapies are in effective or not tolerated
- Used as off-label in patients with focal seizures <6 years of age
- Classification: Carboxamide derivative
Felbamate
- Used as adjunctive treatment for seizure associated with Lennox-Gastaut syndrome if all antiepileptic medications have been deemed ineffective
- May be considered as an add-on agent for tonic or atonic seizures
Fosphenytoin
- Used as an alternative 2nd-line agent in the treatment of status epilepticus
Gabapentin
- Used as adjunctive treatment for SeLEAS and COVE
- Should be avoided in absence and myoclonic seizures, tonic or atonic seizures, Dravet syndrome, Lennox-Gastaut syndrome, idiopathic generalized epilepsy, epilepsy with myoclonic-atonic seizures (Doose syndrome), and juvenile myoclonic epilepsy
- Classification: Gamma-aminobutyric acid (GABA) analogue
Lacosamide
- Used as tertiary treatment for refractory focal onset seizure, SeLEAS, and COVE if adjunctive therapies are ineffective or not tolerated
- Used as off-label in patients <4 years of age
- Used as 2nd-line add-on treatment in patients with generalized tonic-clonic seizures, 3rd-line treatment in patients with focal seizures, but as off-label in patients <4 years of age
- Should be avoided in patients with Dravet syndrome and Lennox-Gastaut syndrome
Perampanel
- Used as adjunctive treatment for patients ≥12 years of age with generalized tonic-clonic seizures, and focal seizures, and as tertiary therapy for idiopathic generalized epilepsies
- Used off -label in patients with generalized tonic-clonic seizures <2 years old if used as add-on treatment, with focal seizures <4 years of age, and with idiopathic generalized epilepsies <7 years of age
- Classification: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist
Phenobarbital (Phenobarbitone)
- Tertiary treatment option for patients with refractory focal onset seizures, generalized tonic-clonic, myoclonic seizure, neonatal seizure, SeLEAS, COVE, and status epilepticus
- Consider as a last-line agent; may have adverse effect on patient’s cognition
- Should be avoided in absence seizures, Dravet syndrome, and Lennox-Gastaut syndrome
- Classification: Barbiturate
Phenytoin
- Tertiary treatment option for patients with refractory focal onset seizures, SeLEAS, COVE, and status epilepticus
- Valproate and Carbamazepine may be preferred since they tend to have fewer adverse effects
- Also recommended as 2nd-line IV therapy for patients with convulsive status epilepticus if unresponsive to 2 doses of benzodiazepine
- Should be avoided in absence seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, and epilepsy with myoclonic-atonic seizures (Doose syndrome)
- Classification: Hydantoin compound
- Associated with gum hypertrophy
Pregabalin
- Used as tertiary treatment for patients with SeLEAS and COVE
- Should be avoided in absence seizures, tonic or atonic seizures, idiopathic generalized epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, and epilepsy with myoclonic-atonic seizures (Doose syndrome)
- Classification: GABA analogue
Primidone
- Used as tertiary treatment for generalized tonic-clonic seizures
- Classification: Barbiturate, related to Phenobarbital and partially metabolized to Phenobarbital
Rufinamide
- Used as tertiary treatment for generalized tonic or atonic seizures, and adjunctive therapy for Lennox-Gastaut syndrome in children ≥4 years old
- Used off-label as 3rd-line add-on treatment in patients with Lennox-Gastaut syndrome <1 year of age
- Classification: Carboxamide derivative
Stiripentol
- Used as adjunctive treatment for patients with Dravet syndrome
- Classification: GABA analogue
Tiagabine
- Used as tertiary therapy for refractory focal onset seizures, SeLEAS and COVE
- Used off-label in patients with focal seizures <12 years of age
- Should be avoided in generalized tonic-clonic, absence and myoclonic seizures, tonic or atonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome
- Classification: Nipecotic acid derivative
Vigabatrin
- Used as tertiary therapy for refractory focal seizure, SeLEAS and COVE
- Should be reserved for patients not adequately controlled by other agents
- 1st-line treatment for patients with infantile spasms that may or may not be due to tuberous sclerosis
- Combination with high-dose oral Prednisolone should be considered in patients with infantile spasms not due to tuberous sclerosis, except in children at high risk of steroid-related side effects
- Should be avoided in generalized tonic-clonic, absence and myoclonic seizures, tonic or atonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, and epilepsy with myoclonic-atonic seizures (Doose syndrome)
- Associated with visual field impairment in adults but few data exist in pediatric patients
- Classification: GABA analogue
Zonisamide
- Used off-label as 2nd-line or add-on treatment in patients with focal seizure <6 years of age
- Classification: Benzisoxazole derivative
Benzodiazepines
Use of benzodiazepines may be limited by development of tolerance and sedation; other antiepileptics are usually preferred
Clobazam
- Recommended as adjunctive treatment for patients with generalized tonic-clonic seizures, myoclonic seizures, tonic or atonic seizures, epilepsy with myoclonic-atonic seizures (Doose syndrome), SeLEAS, COVE, and Lennox-Gastaut syndrome
- Used off-label in patients <6 months of age with generalized tonic-clonic seizures, myoclonic seizures, tonic or atonic seizure, Dravet syndrome, Lennox-Gastaut syndrome, and epilepsy with myoclonic-atonic seizures (Doose syndrome), and in tonic or atonic seizure when used as monotherapy
- Used in combination with Cannabidiol as a 2nd-line add-on treatment option in Dravet syndrome, and as a 3rd-line add-on treatment option in Lennox–Gastaut syndrome
- Also used as tertiary treatment for patients with idiopathic generalized epilepsy, juvenile myoclonic epilepsy, and Dravet syndrome
- Actions: Long-acting benzodiazepine with similar actions to Diazepam
Clonazepam
- Used as an alternative to other antiepileptics in status epilepticus
- Actions: Long-acting benzodiazepine with similar actions to Diazepam
Diazepam
- Used as an adjunctive treatment for all types of seizures and status epilepticus
- Actions: Long-acting benzodiazepine which acts by enhancing GABA activity in the brain
Lorazepam
- Used as 1st-line agent in the treatment of status epilepticus
- Advantageous to Diazepam in status epilepticus because it has a longer duration of action
- Disadvantage: Parenteral form requires refrigeration
- Actions: Long-acting benzodiazepine with similar actions to Diazepam
Midazolam
- Used to treat status epilepticus resistant to treatment by Diazepam, Lorazepam and Phenytoin
- Actions: Short-acting benzodiazepine with similar actions to Diazepam
Other Options
Potassium bromide
- Used in patients with Dravet syndrome resistant to all other treatment options
Prednisolone
- Used as 1st-line treatment for patients with infantile spasms without tuberous sclerosis
Propofol
- As an anesthetic, it is used in conjunction with assisted ventilation to control refractory status epilepticus
- Not to be used for patients on ketogenic diet
- Actions: Short-acting anesthetic
Sulthiame (Sultiame)
- Used as tertiary or adjunctive treatment for SeLECTS
Non-Pharmacological Therapy
Vagus Nerve Stimulation
- Adjunctive intervention to reduce frequency of seizures in patients with focal to bilateral tonic-clonic or generalized onset seizures refractory to anticonvulsants
- Optional treatment for patients with contraindications for surgery
Nutrition
- A ketogenic diet may help in the management of pediatric patients with tonic or atonic seizures, Dravet syndrome, Lennox-Gastaut syndrome, infantile spasms, status epilepticus, Doose syndrome, and epilepsy associated with pyruvate dehydrogenase deficiency
- Studies have shown marked reduction in seizure frequency in children on high fat, low carbohydrate controlled protein (ketogenic) diet
- Modified Atkins diet and low glycemic index treatment may also be considered as an alternative to ketogenic diet
Psychological Interventions
- Eg relaxation techniques, cognitive behavior therapy
- May be helpful in pediatric patients with focal epilepsy
Treatment Maintenance
- Routine level monitoring of anti-epileptic drug is not recommended in patients but may be considered
- Continue treatment for 2-5 years
- If patient is seizure-free after 2-5 years, drug withdrawal may be considered based on patient preference, seizure type and history
- Withdraw treatment gradually, over a few months, to prevent recurrent seizures
- Patients already receiving anticonvulsant drugs who present with an unexplained seizure should have an anticonvulsant level checked
- Withdraw 1 drug at a time in combination therapy