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 as 1st-line therapy for newly diagnosed focal seizures and 1st-line therapy option for patients with primary generalized tonic-clonic seizures unresponsive or with contraindications to Valproate therapy
• Also used as 1st-line treatment for patients with benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• Also used as adjunctive treatment for focal seizures and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) 
• Should be avoided in absence, myoclonic, tonic and atonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy and Lennox-Gastaut 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
• Classification: Succinimide compound

Lamotrigine

• Used as 1st-line therapy for newly diagnosed focal seizures, primary generalized tonic-clonic and absence seizures, and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
  • Treatment option for patients with absence seizures unresponsive to Ethosuximide or Valproate
• May also be used as 1st-line treatment for idiopathic generalized onset epilepsy and juvenile myoclonic epilepsy if Valproate is ineffective or not tolerated
• Also used as adjunctive treatment for focal seizures, generalized tonic or atonic seizure, Lennox-Gastaut syndrome, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) and as tertiary therapy for myoclonic seizures
• Also used in childhood or juvenile absence epilepsy in combination with Ethosuximide or Valproate if unresponsive to 2 1st-line antiepileptic drugs
  • Use of Valproate for girls with childbearing potential should be avoid
• Classification: Phenyltriazine compound

Levetiracetam

• Used as 1st-line therapy option for newly diagnosed focal seizures, primary generalized myoclonic seizures, idiopathic generalized epilepsy, and juvenile myoclonic epilepsy
• Also used as adjunctive treatment for focal seizures, primary generalized tonic-clonic seizures, myoclonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) and tertiary therapy for absence seizures
• Also recommended as 2nd-line therapy for patients with benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) if treatment failure with Carbamazepine or Lamotrigine occurs
• Classification: Analogue of Piracetam which is a nootropic

Oxcarbazepine

• Used as alternative 1st-line monotherapy for newly diagnosed focal to bilateral tonic-clonic seizure, for primary generalized tonic-clonic seizures benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
  • At 2400 mg/day, was shown to be effective in monotherapy for refractory focal epilepsy
• Recommended as adjunctive treatment for patients with focal seizures, benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• 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, Lennox-Gastaut syndrome, idiopathic generalized epilepsy, juvenile myoclonic epilepsy and myoclonic seizures
• Classification: 10-keto analogue of Carbamazepine

Topiramate

• Used as first-line monotherapy in patients with generalized myoclonic seizures, in newly diagnosed patients with epilepsy, or conversion to monotherapy, or as adjunctive treatment for newly diagnosed focal seizure, generalized tonic-clonic seizures, myoclonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
  • Also used as tertiary treatment for patients with generalized absence and tonic or atonic seizures
  • In some countries, Topiramate is only approved as adjunctive treatment
• May also be used as 1st-line treatment for idiopathic generalized epilepsy, myoclonic epilepsy of infancy, juvenile myoclonic epilepsy, and patients with Dravet syndrome
• 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, myoclonic seizures, tonic or atonic seizures, all generalized seizures, and idiopathic generalized epilepsy
• May also be used as 1st-line therapy for juvenile myoclonic epilepsy, Dravet syndrome, Lennox-Gastaut syndrome and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• Also used as adjunctive treatment for focal seizures, generalized tonic-clonic seizures, myoclonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• 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

• Recently approved as monotherapy or adjunctive therapy for focal onset seizures in patients ≥4 years old as oral therapy and for patients ≥16 years old as both oral and intravenous therapy
• Classification: 2-pyrrolidine derivative and Levetiracetam analog

Eslicarbazepine acetate

• Used as tertiary treatment for refractory focal seizure and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) if adjunctive therapies are ineffective or not tolerated
• Classification: Carboxamide derivative

Felbamate

• Used as adjunctive treatment for seizure associated with Lennox-Gastaut syndrome if all antiepileptic medications have been deemed ineffective

Gabapentin

• Used as adjunctive treatment for focal seizure and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• Should be avoided in absence and myoclonic seizures, Lennox-Gastaut syndrome, idiopathic generalized epilepsy and juvenile myoclonic epilepsy
• Classification: Gamma-aminobutyric acid (GABA) analogue

Lacosamide

• Used as tertiary treatment for refractory focal onset seizure and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) if adjunctive therapies are ineffective or not tolerated

Perampanel

• Used as adjunctive treatment for patients ≥12 years of age with generalized tonic-clonic seizures and as tertiary therapy for focal epilepsy
• Classification: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist

Phenobarbital (Phenobarbitone)

• Tertiary treatment option for patients with focal onset seizures, generalized tonic-clonic, tonic and atonic seizures, neonatal seizure, benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type), and status epilepticus
• Consider as a last-line agent; may have adverse effect on patient’s cognition
• Should be avoided in absence seizures
• Classification: Barbiturate

Phenytoin

• Tertiary treatment option for patients with focal onset seizures, generalized tonic-clonic seizures, benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type) and status epilepticus
  • Valproate and Carbamazepine may be preferred since they tend to have fewer adverse effects
• Should be avoided in absence seizures, idiopathic generalized epilepsy and juvenile myoclonic epilepsy 
• Classification: Hydantoin compound
• Associated with gum hypertrophy

Pregabalin

• Used as tertiary treatment for patients with refractory focal onset seizures and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• Should be avoided in absence seizures, tonic or atonic seizures, idiopathic generalized epilepsy, Lennox-Gastaut syndrome and juvenile myoclonic epilepsy
• Classification: GABA analogue

Primidone

• Used as tertiary treatment for focal onset seizures, and 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
• 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 and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• Should be avoided in generalized tonic-clonic, absence and myoclonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy and Lennox-Gastaut syndrome
• Classification: Nipecotic acid derivative

Vigabatrin

• Used as tertiary therapy for refractory focal seizure and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
  • 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
• Should be avoided in generalized tonic-clonic, absence and myoclonic seizures, idiopathic generalized epilepsy and juvenile myoclonic epilepsy
• Associated with visual field impairment in adults but few data exist in pediatric patients
• Classification: GABA analogue

Zonisamide

• Used as tertiary treatment for refractory focal seizure, generalized absence, myoclonic seizures and benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type)
• Also used as adjunctive treatment for juvenile myoclonic epilepsy, idiopathic generalized epilepsy and refractory focal epilepsy
• 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 focal seizures, generalized tonic-clonic seizures, benign epilepsy associated with centrotemporal spikes, Panayiotopoulos syndrome, or late-onset childhood occipital epilepsy (Gastaut type), and Lennox-Gastaut syndrome
• Also used as tertiary treatment for patients with generalized absence, myoclonic seizures, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, and Dravet syndrome
• Actions: Long-acting benzodiazepine with similar actions to Diazepam

Clonazepam

• Also used as tertiary treatment for focal to bilateral tonic-clonic seizure, generalized absence seizures, generalized myoclonic seizures, idiopathic generalized epilepsy and juvenile myoclonic epilepsy
• 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

Nitrazepam

• Used to treat epilepsy especially infantile spasm
• Actions: Intermediate-acting benzodiazepine with similar actions to Diazepam

Others

Acetazolamide

• Used as adjunctive treatment for refractory focal to bilateral tonic-clonic seizure, atypical absence, tonic, atonic and myoclonic seizures resistant to conventional treatment
• Actions: Inhibits carbonic anhydrase in glial cells in central nervous system (CNS)

Paraldehyde

• Used to treat status epilepticus resistant to conventional treatment
  • Use is limited by the hazards associated with its administration
• Actions: Sedative and hypnotic with antiepileptic effects

Piracetam

• Used as tertiary treatment for patients with generalized myoclonic seizures
• Actions: Nootropic with CNS protective properties against hypoxia

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
• Actions: Short-acting anesthetic

Tetracosactide

• Also recommended for patients with non-tuberous sclerosis-caused infantile spasms

Thiopental sodium

• Treatment option for patients with refractory convulsive status epilepticus
• Actions: Short-acting barbiturate anesthetic

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
  • 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