epilepsy
EPILEPSY
Epilepsy is a clinical multiaxial diagnosis.
Epileptic seizure is a transient occurrence of signs/symptoms brought about by abnormal excessive or synchronous neuronal activity in the brain.
It is recommended that all patients having a first seizure be referred as soon as possible to a specialist to ensure accurate and early diagnosis and initiation of treatment appropriate to the needs of the patients.

Principles of Therapy

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

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 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 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

Single Generalized Tonic-Clonic Seizure
  • Patient could be given treatment with anticonvulsant if:
    • 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

 

Pharmacotherapy

Anticonvulsants

Choice of anticonvulsant drugs will be based on their indications, adverse effects and interaction profiles

Barbiturates

Phenobarbital (Phenobarbitone)

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

Primidone

  • Used to treat focal seizures and generalized tonic-clonic seizures

Carboxamides

Carbamazepine

  • Used to treat focal seizures with or without secondary generalized seizure and primary generalized tonic-clonic seizures
  • Should be avoided in absence, myoclonic, tonic and atonic seizures

Oxcarbazepine

  • Used as 1st-line monotherapy or as adjunctive treatment for generalized tonic-clonic seizures and focal seizures and drug-resistant epilepsy
    • At 600-2400 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, myoclonic, tonic and atonic seizures

Rufinamide

  • Approved as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in children ≥4 years old

Fatty Acid Derivatives

Tiagabine

  • Used as 2nd-line drug or adjunctive treatment for focal seizures and drug-resistant epilepsy
  • Should be avoided in generalized tonic-clonic, absence and myoclonic seizures
  • Classification: Nipecotic acid derivative

Valproate (Divalproex, Valproic Acid)

  • Used to treat focal seizures and generalized seizures including absence, myoclonic and atonic seizures
  • Classification: Carboxylic acid derivative

Gamma-aminobutyric acid (GABA)-Analogue

Gabapentin

  • Used as 2nd-line monotherapy or as adjunctive treatment for focal seizures and drug-resistant epilepsy
  • Should be avoided in absence and myoclonic seizures

Pregabalin

  • Used as adjunctive treatment for focal seizures
  • Should be avoided in absence and myoclonic seizures

Vigabatrin

  • Used as adjunctive treatment for resistant focal seizures, infantile spasm and drug-resistant epilepsy
    • Should be reserved for patients not adequately controlled by other agents
  • Preferred treatment for infantile spasms and West syndrome
  • Should be avoided in generalized tonic-clonic, absence and myoclonic seizures
  • 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, generalized tonic-clonic seizures and status epilepticus

Other Anticonvulsants

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 anticonvulsant activity 

Lacosamide

  • Used as monotherapy and/or an adjunctive treatment for focal onset seizures in adults
  • Studies have shown that it enhances the slow inactivation of sodium channels that in turn stabilizes hyperexcitable neuronal membranes and inhibits repetitive neuronal firing

Lamotrigine

  • Used as monotherapy or as adjunctive treatment for focal seizures, generalized tonic-clonic, absence, tonic and atonic seizures and Lennox-Gastaut syndrome
  • 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
  • Classification: Phenyltriazine compound

Levetiracetam

  • Used as adjunctive treatment for focal onset seizures, generalized tonic-clonic, myoclonic, tonic and atonic seizures, and drug-resistant epilepsy
  • 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
  • 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

Retigabine

  • Used as adjunctive treatment for focal onset seizures in adults
  • A neuronal potassium channel opener that reduces neuronal activity that will stabilize the resting membrane potential and controls the electrical excitability in neurons
  • Also called Ezogabine

Topiramate

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

Zonisamide

  • Used as monotherapy or adjunctive treatment for focal onset seizures
  • 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 drug-resistant idiopathic epilepsy
  • Actions: Long-acting benzodiazepine with similar actions to Diazepam

Clonazepam

  • Used as monotherapy or as an adjunctive treatment for all types of seizures including as an alternative to other antiepileptics in status epilepticus and for refractory myoclonic seizures
  • 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 gamma-aminobutyric acid (GABA) activity inthe 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  


Treatment Maintenance

  • Continue treatment for 2-5 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 one 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

Combination Therapy

  • If monotherapy with 2 drugs fails, try combination therapy using drugs with different mechanisms of action, known synergistic effects and, preferably, different side effects
  • If various combinations fail to confer seizure freedom, return to the combination with the best control of seizures and best tolerability
  • Consider combination therapy if:
    • Patient has substantial seizure control with 1st-line agent but still experiences seizures at maximum dose
  • Drugs used in combination should be matched to patient’s seizure type
  • 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

Refractory Epilepsy Therapy

  • Best predictor of drug-resistant epilepsy is failure to control seizures with 1st well-tolerated antiepileptic drug given a correct diagnosis of epilepsy
  • Before changing therapy, review diagnosis, drug dose, drug administration frequency, comorbidities and patient compliance

Surgical Intervention

Surgery

  • May be an option for epileptic patients with seizures uncontrolled by pharmacological therapy and those with surgically remediable epileptic syndrome
  • Assess patient for the suitability of curative resective procedures before considering palliative procedures

Curative Resective Procedures

  • Anterior and medial temporal lobe resection
    • Approximately 70-90% of the patients become seizure-free
  • Resection of epileptogenic focus based on video-electroencephalogram recording of actual habitual seizures, neuropsychological tests, magnetic resonance imaging and positron emission tomography scan
    • Approximately 50% of the patients become seizure-free

Palliative Procedures

  • Corpus callosotomy - for uncontrolled frequent drop attacks
  • Subpial transection - for epileptic focus at eloquent functional area

Vagus Nerve Stimulation

  • Reduces frequency of seizures in patients refractory to pharmacological therapy and who are not suitable for surgery
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