Epilepsy%20(pediatric) Treatment

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

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

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

• 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