Epilepsy Treatment

In most clinical settings, seizures are not treated unless ≥2 unprovoked seizures are demonstrated within a 12-month period

• Detailed history needs to be taken to rule out any previous absence, myoclonic or focal seizures because patients with undiagnosed epilepsy may present with a single generalized tonic-clonic 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 electroencephalography or have congenital neurological deficits or structural brain lesion
  • Lowest recurrence risk rates (13-40%) are in patients who experience acute symptomatic seizures (provoked) or those with a normal electroencephalography and no identifiable cause for seizures
  • Overall risk is 30-40% which is greatest during the 1st year and decreases to <10% after 2 years
• Treatment with antiepileptics/anticonvulsants can reduce the risk of recurrence by half
  • Early treatment has not been shown to alter the prognosis of epilepsy
• Decision to start the therapy should be made by the patient and the epilepsy specialist after the discussion of the risks, benefits, preferences, and prognosis
• Treatment should be individualized

• Patient could be given treatment with antiepileptics/anticonvulsants if:
  • Patient has history of previous myoclonic, absence or focal seizures
  • Electroencephalography shows unequivocal epileptic discharges
  • Patient has congenital neurological deficit
  • Patient decides the risk of recurrence not acceptable
  • A structural abnormality was demonstrated in brain imaging

Antiepileptic Drugs/Anticonvulsants

Choice of antiepileptics/anticonvulsants will be based on their indications, comorbidity, adverse effects and interaction profiles

Barbiturates

Phenobarbital (Phenobarbitone)

• Treatment option for focal onset seizures, generalized tonic-clonic, tonic and atonic seizures, myoclonic seizure, neonatal seizures and status epilepticus
• Should be avoided in absence seizures, Dravet syndrome and Lennox-Gastaut syndrome
• An enzyme inducer, can accelerate the metabolism of many lipid-soluble drugs and has an impact on bone health

Primidone

• Used as an add-on to treat focal seizures and generalized tonic-clonic seizures

Carboxamides

Carbamazepine

• Used to treat focal seizures with or without secondary generalized seizure
• Should be avoided in absence, myoclonic, tonic, atonic seizures, Dravet syndrome and Lennox-Gastaut syndrome

Eslicarbazepine acetate

• May be effective as an adjunctive therapy or as monotherapy in reducing seizure frequency in patients with treatment-resistant adult focal epilepsy
• Mechanism of action is through use-dependent blockage of voltage-sensitive sodium channels

Oxcarbazepine

• Used as 1st-line monotherapy or as adjunctive treatment for focal seizures
• Extended-release (2400 mg/day) is shown to be possibly effective for treatment-resistant adult 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, myoclonic, tonic, atonic seizures, Dravet syndrome and Lennox-Gastaut syndrome

Rufinamide

• Approved as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in adults and children ≥4 years old
• Can be considered established as effective for decreasing seizure frequency in treatment-resistant adult focal epilepsy
• Mechanism of action is through use-dependent blockage of voltage-sensitive sodium channels

Fatty Acid Derivatives

Tiagabine

• Used as adjunctive treatment for treatment-resistant focal epilepsy
• Should be avoided in generalized tonic-clonic, absence, myoclonic seizures, Dravet syndrome and Lennox-Gastaut syndrome
• Classification: Nipecotic acid derivative

Valproate (Divalproex, Valproic acid)

• Used to treat focal seizures and generalized seizures including absence, idiopathic, myoclonic and atonic seizures
  • Consider as first-line treatment for absence seizure at risk of or with other seizure types
  • Can be used to men and women who are unable to have children
• Classification: Carboxylic acid derivative

Gamma-aminobutyric acid (GABA)-Analogue

Gabapentin

• Used as 2nd-line monotherapy or as adjunctive treatment for focal seizures
• May be considered in decreasing frequency of seizures in patients ≥60 years old with new-onset focal epilepsy
• Should be avoided in absence, myoclonic seizures, Dravet syndrome and Lennox-Gastaut syndrome

Pregabalin

• Used as adjunctive treatment for focal seizures
• Immediate-release formulation is recommended as an adjunctive treatment to reduce seizure frequency in treatment-resistant adult focal epilepsy
• Binds to the α2-δ protein subunit of voltage-gated calcium channels
• Should be avoided in absence, myoclonic seizures, Dravet syndrome and Lennox-Gastaut syndrome

Vigabatrin

• Used as adjunctive treatment for treatment-resistant adult focal epilepsy
  • Should be reserved for patients not adequately controlled by other agents
• Preferred treatment for infantile spasms and West syndrome
• Should be used with caution in patients with absence, myoclonic seizures, Dravet syndrome and Lennox-Gastaut syndrome
• Acts by inactivating gamma-aminobutyric acid (GABA) transaminase
• Limited clinical use because of irreversible concentric visual field defects

Hydantoins

Fosphenytoin

• Used to treat status epilepticus
  • Advantages over standard parenteral Phenytoin eg easier administration (intramuscular/intravenous with less tissue irritation at injection site) and better tolerability (less incidence of hypotension and cardiac arrhythmias compared to Phenytoin)

Phenytoin

• Used to treat focal onset seizures and status epilepticus
• Should be used with caution in patients with absence and myoclonic seizures

Other Antiepileptic Drugs/Anticonvulsants

Brivaracetam

• Recently approved as monotherapy or adjunctive therapy for focal onset seizures in patients ≥16 years old
• May be used as monotherapy or add-on for myoclonic seizure
• May be used as an add-on for generalized tonic-clonic seizure
• Classification: 2-pyrrolidine derivative and Levetiracetam analog

• Approved for the treatment of focal seizures

Ethosuximide

• Used to treat absence seizures
• Classification: Succinimide compound

Felbamate

• May be used as monotherapy or as adjunctive treatment for refractory focal seizures
  • Last-line therapy for patients in whom epilepsy is so severe that risk of aplastic anemia and/or liver failure is acceptable
• Classification: Carbamate structurally related to Meprobamate with antiepileptic activity 

Lacosamide

• Used as monotherapy and/or an adjunctive treatment for focal onset seizures in adults
  • Has shown effectivity in reducing seizure frequency in patients with treatment-resistant adult focal epilepsy
• Used as adjunctive treatment for generalized tonic-clonic seizure
• Inactivates slowly voltage-gated channels and binds to collapsin response mediator protein 2 (CRMP-2)
• May exacerbate seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome

Lamotrigine

• Used as monotherapy or as adjunctive treatment for focal seizures, generalized tonic-clonic, absence, tonic and atonic seizures and Lennox-Gastaut syndrome
  • May be a treatment option to reduce seizure frequency in patients ≥60 years old with new-onset focal epilepsy or unclassified generalized tonic-clonic seizures
  • Extended-release and immediate-release formulations may be used as an adjunctive therapy to reduce seizure frequency in treatment-resistant generalized tonic-clonic seizures
  • Can be used in women who are able to have children
• Has favorable behavioral and cognitive profile
• Does not induce metabolism of lipid-soluble drugs and does not lead to weight gain
• Can worsen myoclonus in some cases
• May exacerbate seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome
• Classification: Phenyltriazine compound

Levetiracetam

• Used as adjunctive treatment for focal onset seizures, generalized tonic-clonic, myoclonic, tonic and atonic seizures, and drug-resistant epilepsy
  • Can be used in women who are able to have children
• May be used as monotherapy in adults for focal onset seizures with or without secondary generalization
• Classification: Analogue of Piracetam which is a nootropic

Methsuximide

• Used to treat absence seizures
• Classification: Succinimide compound

Perampanel

• Used as adjunctive treatment for focal onset seizures in adults and generalized tonic-clonic seizures
• Recommended as an adjunctive therapy to reduce seizure frequency in treatment-resistant adult focal epilepsy
• Inhibits alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced increases in the intracellular Ca⁺² and selectively blocks AMPA-receptor mediated synaptic transmission, thus reducing neuronal excitation

Topiramate

• Used as monotherapy in newly diagnosed epilepsy or conversion to monotherapy in patients with epilepsy
• Adjunctive treatment for focal seizures, generalized seizures and Lennox-Gastaut syndrome
  • In some countries, Topiramate is only approved as adjunctive treatment
• In children, may be used as 1st-line treatment for myoclonic epilepsy of infancy
• Extended-release Topiramate was found to be probably effective as adjunctive therapy for treatment-resistant adult focal epilepsy
• Classification: Sulfamate-substituted monosaccharide

Zonisamide

• Recommended as initial monotherapy or add-on treatment for adults with focal onset seizures 
• May be used as monotherapy to reduce seizure frequency in patients with new-onset focal epilepsy or unclassified generalized tonic-clonic seizures
• May be an option as an adjunctive therapy to reduce seizure frequency in children ages 6-17 years with treatment-resistant focal epilepsy
• A benzisoxazole derivative that appears to have mechanism of action to stop the spread of seizures and suppresses their focus

Benzodiazepines

Use of benzodiazepines may be limited by development of tolerance and sedation; other antiepileptics are usually preferred

Clobazam

• Used as adjunctive treatment for focal onset seizures, generalized seizures, Lennox-Gastaut syndrome and may be effective for drug-resistant adult focal epilepsy
• Actions: Long-acting benzodiazepine with similar actions to Diazepam

Clonazepam

• Used as monotherapy or as an adjunctive treatment for all types of seizures (except absence and myoclonic seizures) including as an alternative to other antiepileptics in status epilepticus and for refractory myoclonic seizures and for drug-resistant idiopathic generalized epilepsy
• Actions: Long-acting benzodiazepine with similar actions to Diazepam

Diazepam

• Used as an adjunctive treatment for all types of seizures and may be used as 1st-line agent in the treatment of 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

Pinazepam

• Used as adjunctive treatment for epilepsy
• Actions: Long-acting benzodiazepine with similar actions to Diazepam

Others
Acetazolamide

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

Propofol

• As an anesthetic, it is used in conjunction with assisted ventilation to control refractory status epilepticus
• Actions: Alkylphenol short-acting anesthetic and central nervous system depressant which directly activates gamma-aminobutyric acid receptor  

• Drug withdrawal may be considered after the patient has been seizure-free for 3-5 years
• Indications for monitoring drug levels:
  • Adjustment of drug dosage (eg Phenytoin)
  • Detection of noncompliance to the prescribed medication
  • Management of pharmacokinetics interactions
  • Suspected toxicity
  • Specific clinical situations (eg status epilepticus, organ failure)
• Predictors of better outcome in terms of remission from seizures:
  • Absence of brain damage
  • Absence of generalized tonic-clonic seizures
  • Absence of generalized epileptiform activity on electroencephalography
• Frequency of seizures in the 1st 6 months after initial presentation is the strongest prognostic indicator
• With therapy, up to 70% of patients can achieve a 5-year remission
• If patient is seizure-free after 2-5 years, drug withdrawal may be considered based on patient preference, seizure type, history, neuroimaging and electroencephalogram findings
• Patients with higher risk of seizure recurrence are those:
  • With more seizures prior to start of therapy
  • With seizures after the start of therapy
  • With neurologic deficits
  • On combination therapy
  • With shorter seizure-free duration
  • With history of myoclonus
  • With abnormal neuroimaging results
• Withdraw treatment gradually, over a few months, to prevent recurrent seizures
• Withdraw 1 drug at a time in combination therapy
• Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years
• Lifestyle modification to reduce stress and increase treatment compliance is suggested

• 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
• Combined antiepileptic drugs should have different mechanisms of action
• Combination therapy should be administered as such:
  • Administer the best monotherapy option at optimal dose with no side effects
  • Administer the subsequent drugs after that, increase dose of each slowly to obtain maximum response with minimal toxicity

• Defined as failure of adequate trials of 2 tolerated and appropriately chosen and used antiepileptic drug schedules to obtain sustained seizure freedom 
• Before changing therapy, review diagnosis, drug dose, drug administration frequency, comorbidities and patient compliance
• A systematic review has showed sufficient evidence that ketogenic diet is effective in reducing seizure frequencyin children with refractory epilepsy although there is a lack of controlled trials
• For patients >18 years old with resistant focal epilepsy, deep brain stimulation may be done
  • It is the electrical stimulation of specific subcortical nuclei that have widespread neural connections