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LeenaKämppi

Treatment of Epilepsy in Adults

Essentials

  • The cornerstone of treating epilepsy is regular, long-term pharmacotherapy to eliminate seizures without significant adverse effects.
  • Antiepileptic pharmacotherapy should be started as soon as the risk of recurring epileptic seizures has been established and epilepsy has been diagnosed.
  • It is more important to monitor the patient's general status and mental health than laboratory values.
  • The diagnosis of epilepsy, aetiological investigations, choice of medication and follow-up of response to medication and its suitability are done in a neurology unit in specialized care.
  • Long-term follow-up of adults with well controlled epilepsy can be carried out in primary care.
  • Patients with severe epilepsy should be monitored in specialized care. The possibilities for surgical treatment should be assessed sufficiently early in a centre specializing in epilepsy surgery.

General remarks

  • An epileptic seizure is a transient disturbance in brain function that is due to abnormal, excessive or synchronized electrical neuronal activity in brain areas of varying size.
  • Epilepsy is a disease in which the brain has a chronic tendency to spontaneously produce epileptic seizures, and patients may additionally have other problems in neurological, cognitive, mental or social performance in consequence of the disease.
  • With medication, about 70% of the patients become seizure-free while 20-30% of patients have treatment-resistant epilepsy.
  • Epilepsy is classified as treatment-resistant if despite two appropriately chosen and used antiepileptics there are significant epileptic symptoms affecting daily life, such as repeated seizures, cognitive or behavioural problems, delayed development or adverse treatment effects.
  • Patients with epilepsy have a 2-3-fold risk of death compared to the normal population. Treatment-resistant epilepsy increases the risk of sudden unexpected death in epilepsy (SUDEP).
  • Treatment should be provided considering not only the actual seizures but also the aetiology of the epilepsy and the available treatments. The patient's situation should be considered comprehensively, taking into account any effects of the disease on his/her functional capacity and any need for medical or vocational rehabilitation.

Chain of treatment

  • Specialized care is responsible for:
    • diagnosing epilepsy
    • choosing antiepileptic medication and monitoring the response to and suitability of medication
    • deciding on stopping medication
    • determining the ability to drive or to work, performing assessments for rehabilitation
    • follow-up during pregnancy; this also applies to patients without seizures
    • follow-up of patients with seizures or severe epilepsy, and treatment decisions for such patients.
  • Long-term follow-up of adults with well controlled epilepsy can be done in primary care.
    • When follow-up is transferred to primary care, a written treatment plan and follow-up instructions should be recorded individually for each patient in the final neurological assessment.
    • Reactivation of seizures, challenges or adverse effects related to pharmacotherapy, an active wish to get pregnant or pregnancy are indications for referral for reassessment in specialized care.
  • Assessment of the treatment of severe epilepsy should be done in a tertiary care hospital. Assessment related to epilepsy surgery should be performed in a centre specializing in such surgery.
  • Find out about locally relevant chain of treatment.

Pharmacotherapy

  • The goal of drug therapy is absence of seizures without significant adverse effects.
  • Drug therapy should be initiated when epilepsy is diagnosed, i.e. when the patient has had two or more epileptic seizures within a year without obvious predisposing factors or if a chronic predisposing factor was found in the brain in association with the first seizure and the risk of recurrence is high Immediate Antiepileptic Drug Treatment, Versus Placebo, Deferred, or No Treatment for First Unprovoked Seizure.
  • Find out about local reimbursement policies concerning antiepileptic drugs.

Choice and follow-up of pharmacotherapy

  • Epilepsies are divided into focal and generalized epilepsies based on type of seizure.
  • Antiepileptic treatment should be started with a primary drug chosen depending on the type of epilepsy and seizure (see Antiepileptic drugs).
  • Some drugs, such as oxcarbazepine and carbamazepine, are only suitable for focal epilepsy, but most drugs are broad spectrum drugs effective against all types of epilepsy and seizures. However, the response varies individually.
  • When choosing the drug, the patient's gender and chances of / plans for getting pregnant should be considered. Valproate, for example, should in principle not be used for women of fertile age due to the risk of fetal damage Monotherapy Treatment of Epilepsy in Pregnancy: Congenital Malformation Outcomes in the Child.
  • The aim is to find the lowest effective dose that prevents seizures. The dose should always be tailored individually.
  • Patients should be contacted 2-8 weeks after beginning medication to assess the response and any adverse effects.
  • Freedom from seizures and tolerability of the medication are most important, not serum drug concentrations Therapeutic Monitoring of Antiepileptic Drugs for Epilepsy. Drug concentrations rarely need to be monitored in long-term follow-up.
  • At the beginning of treatment and when increasing the dose, safety blood tests (basic blood count with platelet count, Na, ALT) should be done for oxcarbazepine, carbamazepine, valproate and phenytoin, for example. Routine follow-up with safety blood tests is not needed.
  • If the patient continues to have random seizures when on appropriate medication, the dosage should primarily be increased. If non-compliance or significant alcohol abuse is found as a predisposing factor, instead of increasing the dosage, improving commitment to treatment or supporting the patient in weaning from alcohol should be preferred instead of increasing the dosage Strategies for Improving Adherence to Antiepileptic Drug Treatment in Epilepsy, Care Delivery and Self-Management Strategies for Adults with Epilepsy.
  • If seizures continue despite medication, a combination of several drugs may be necessary. Combination therapy aims to combine the different mechanisms of action of various drugs, avoiding drugs with similar adverse effects, and utilizing their secondary indications in the treatment of concomitant diseases, such as migraine or neuropathic pain.
  • Some antiepileptic drugs have numerous interactions, which should be considered when planning other medication.
  • As antiepileptic medication (enzyme inducers, in particular) is associated with an increased risk of osteoporosis, use of vitamin D is recommended.

Adverse effects

  • In the starting and escalation phases, adverse effects often occur, particularly CNS effects (fatigue, dizziness, nausea) that are usually mild and subside spontaneously within a few weeks (for more detail, see Antiepileptic drugs).
  • Such effects can often be alleviated by starting the medication at a low dose and gradually increasing the dose.
  • When starting medication, symptoms suggestive of rare severe adverse effects should be discussed with the patient, and the patient should be advised to contact the treating unit immediately should such symptoms occur. Particularly symptoms requiring change of medication should be mentioned:
    • hypersensitivity reactions (rashes)
    • symptoms of liver damage (vomiting, abdominal pain)
    • mental adverse effects (depression, aggressiveness, self-destructiveness).
  • Drugs may cause abnormal blood levels. Mild leucocytopenia (up to 2 × 109 /l), increased liver enzyme concentrations (ALT up to 2-3 × lower limit of reference range) and mild hyponatraemia (Na 128-135 mmol/l) are common, not predictive of more severe adverse effects and, if asymptomatic, do not warrant further measures. Levels differing significantly from the reference ranges are indications for changing medication.

Antiepileptic drugs

  • Antiepileptic drugs are divided into first- and second-line drugs according to clinical and reimbursement criteria.
    • Find out about local reimbursement policies and their possible impact on the division indicated below.
  • Here, we list for each drug the principal mechanisms of action, the types of epilepsy/seizures for which they are most suitable, the initial doses and target maintenance doses, the most common adverse effects and other issues to be observed. Use locally available drug information sources for more detailed information.

First-line drugs Lamotrigine Versus Carbamazepine Monotherapy for Epilepsy: an Individual Participant Data Review, Topiramate Versus Carbamazepine Monotherapy for Epilepsy, Carbamazepine Versus Phenytoin Monotherapy for Epilepsy, Oxcarbazepine Versus Carbamazepine Monotherapy for Partial Onset Seizures, Phenytoin Versus Valproate Monotherapy for Partial Onset Seizures and Generalized Onset Tonic-Clonic Seizures, Clobazam Monotherapy for Partial-Onset or Generalized-Onset Seizures

  • Oxcarbazepine
    • Principal mechanism of action: sodium channel blockade
    • Type of seizure: focal onset seizures
    • Initial dose: 150 mg twice daily, dose increments 150 mg/3 days up to 450 mg twice daily
    • Adverse effects: hyponatraemia, dizziness, nausea, allergic reactions
    • Other things to consider
      • Safety blood tests necessary in the beginning
      • Affects the efficacy of oral contraceptives due to its CYP enzyme inducing activity.
  • Carbamazepine
    • Principal mechanism of action: sodium channel blockade
    • Type of seizure: focal onset seizures
    • Initial dose: 100 mg twice daily, dose increments 100 mg/2-3 days up to 300 mg twice daily
    • Adverse effects: rash, dizziness, nausea, hyponatraemia. In long-term use, may affect bone density, hormone production and cholesterol levels.
    • Other things to consider
      • Safety blood tests necessary in the beginning
      • Significant CYP enzyme inducer → must be considered in association with many drugs
  • Valproate
    • Principal mechanism of action: sodium channel blockade and increased GABA effect
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: for modified-release products either 300 mg twice daily or 500 mg twice daily
    • Adverse effects: increased appetite / weight gain, menstrual disturbances, hair loss, tremor, liver damage as a serious adverse effect
    • Other things to consider
      • Safety blood tests necessary in the beginning
      • Significant teratogenic effect; should be avoided in women of fertile age due to risk of fetal damage
      • CYP enzyme inducer → must be considered in association with certain drugs
      • Intravenous preparation also available

Second-line drugs Rufinamide Addon Therapy for Refractory Epilepsy, Pregabalin Add-on for Drug-Resistant Partial Epilepsy, Tiagabine Add-on for Drug-Resistant Partial Epilepsy, Topiramate Add-on for Drug-Resistant Partial Epilepsy, Phenobarbitone Vs. Phenytoin for Partial Onset Seizures and Generalized Onset Tonic-Clonic Seizures, Felbamate as an Add-on Therapy for Refractory Epilepsy

  • LevetiracetamLevetiracetam for Partial Epilepsy in Adults
    • Principal mechanism of action: binds to vesicle protein SV2A
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: 500 mg twice daily
    • Adverse effects: fatigue, dizziness, psychological adverse effects
    • Other things to consider
      • No known interactions with other drugs
      • Intravenous preparation also available
  • LacosamideLacosamide Add-on Therapy for Partial Epilepsy
    • Principal mechanism of action: slow inactivation of voltage-dependent sodium channels
    • Type of seizure: focal onset seizures, also used for generalized seizures
    • Initial dose: 50 mg twice daily, dose increments 100 mg/week up to 100 mg twice daily
    • Adverse effects: dizziness, headaches, nausea
    • Other things to consider
      • No known significant interactions with other drugs
      • Intravenous preparation also available
  • Lamotrigine
    • Principal mechanism of action: sodium channel blockade, effect on the calcium channel
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: in monotherapy, 25 mg once daily, dose increments 25 mg/2 weeks up to 100 mg twice daily
    • Adverse effects: rash (requires withdrawal of the drug), tremor, dizziness, diplopia, worsening myoclonus
    • Other things to consider
      • In combination with carbamazepine or valproate, the initial dosage is different from that in monotherapy.
      • Oral contraceptives and hormone replacement therapy will affect drug concentrations but this will not affect dosage during the pill-free week.
  • Topiramate
    • Principal mechanism of action: sodium channel blockade, GABA-A potentiation, inhibition of glutamate and carbonic anhydrase
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: 25 mg once daily, dose increments 25 mg/week up to 50 mg twice daily
    • Adverse effects: psychological and cognitive effects, depression, irritability, confusion, speech problems, weight loss, renal calculi
    • Other things to consider
      • Other indications to be utilized: migraine
  • ZonisamideZonisamide Add-on for Drug-Resistant Partial Epilepsy
    • Principal mechanism of action: sodium and calcium channel effects, GABA inhibition
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: 25 mg twice daily, dose increments 50 mg/week up to 150 mg twice daily
    • Adverse effects: dizziness, diplopia, anorexia, restlessness, allergic reactions, renal calculi
  • Gabapentin
    • Principal mechanism of action: calcium channel effect, GABA effect
    • Type of seizure: focal onset seizures
    • Initial dose: 300 mg 3 times daily, increase gradually over 3 weeks up to 600 mg 3 times daily
    • Adverse effects: psychological effects, balance problems, fatigue, weight gain, myoclonus
    • Other things to consider
      • Renal failure requires dose adjustment
      • Other indications to be utilized: neuropathic pain
  • PregabalinPregabalin Monotherapy for Epilepsy
    • Principal mechanism of action: calcium channel effect
    • Type of seizure: focal onset seizures
    • Initial dose: 75 mg twice daily, dose increments no more than 150 mg/week up to 300 mg twice daily
    • Adverse effects: fatigue, dizziness, increased appetite
    • Other things to consider
      • No significant interactions with other drugs
      • Other indications to be utilized: neuropathic pain and anxiety
  • EslicarbazepineEslicarbazepine Add-on for Drug-Resistant Partial Epilepsy
    • Principal mechanism of action: sodium channel blockade
    • Type of seizure: focal onset seizures
    • Initial dose: 400 mg once daily, dose increments 400 mg/1-2 weeks up to 1 200 mg once daily
    • Adverse effects: hyponatraemia, dizziness, nausea
    • Other things to consider
      • Resembles oxcarbazepine.
  • Perampanel
    • Principal mechanism of action: AMPA receptor antagonist
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: 2 mg once daily, dose increments 2 mg/4 weeks up to 6 mg once daily
    • Adverse effects: dizziness, fatigue, changed appetite, affective symptoms
    • Other things to consider
      • Due to dizziness occurring as an adverse effect, should be taken in the evening just before going to bed
      • Not recommended for patients with severe kidney or liver failure
      • High doses (12 mg once daily) will affect the efficacy of oral contraceptives.
  • BrivaracetamBrivaracetam Addon Therapy for Drugresistant Epilepsy
    • Principal mechanism of action: binds to vesicle protein SV2A
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: 25 mg twice daily, dose increments 50 mg/week up to 50 mg twice daily, or start with an initial dose of 50 mg twice daily
    • Adverse effects: drowsiness, dizziness, psychological effects (better tolerated than levetiracetam)
    • Other things to consider
      • No known significant interactions with other drugs
      • Intravenous preparation available
  • ClobazamClobazam as Add-on for Refractory Epilepsy
    • Principal mechanism of action: GABA agonist
    • Type of seizure: broad spectrum drug, all types of seizures
    • Initial dose: 5-10 mg once daily, dose increments as tolerated up to 20 mg once daily
    • Adverse effects: fatigue, dizziness, headaches, visual disturbances, nausea, memory problems, psychological effects
    • Other things to consider
      • Can be used intermittently, as necessary.
      • In severe epilepsy, to interrupt seizure clusters
  • Clonazepam
    • Principal mechanism of action: GABA agonist, sodium channel effect
    • Type of seizure: broad spectrum drug, all types of seizures, particularly myoclonus
    • Initial dose: 0.25 mg once or twice daily, dose increments as tolerated up to 3-4 mg/day
    • Adverse effects: fatigue, coordination problems, ataxia, dizziness, visual disturbances
    • Other things to consider
      • Other indications to be utilized: restless legs, anxiety and panic symptoms
      • Tolerance develops gradually; discontinuation of medication is difficult and should be carried out very slowly.
  • Phenytoin
    • Principal mechanism of action: sodium channel blockade
    • Type of seizure: focal onset seizures
    • Initial dose: 100 mg twice daily, usually started as emergency treatment with administration of an intravenous loading dose of fosphenytoin; for long-term use only in special cases
    • Adverse effects: dizziness, nausea, diplopia, allergic reactions, gingival hyperplasia
    • Other things to consider
      • Safety blood tests necessary in the beginning
      • Significant CYP enzyme inducer, must be considered in association with other drugs
      • Intravenous preparation (fosphenytoin) available
      • Saturable elimination, requires exact dosage and follow-up of concentrations

Emergency medication

Treatment of severe epilepsy

  • 20-30% of epilepsies are classified as treatment-resistant, with seizures continuing despite two appropriately chosen and used antiepileptic drugs.
  • Epilepsy not responding to medication is in most cases severe but the problem may also be an incorrect diagnosis, other disease preventing implementation of the treatment or problems related to adherence to the treatment.
  • Patients with severe epilepsy should be referred to a tertiary care hospital neurology unit for consultation. A multiprofessional team specialized in epilepsy can perform more detailed investigations to confirm the type of epilepsy and seizure and to define the aetiology in more detail so as to be able to offer the patient the most effective possible treatment.
  • Some patients with severe focal epilepsy benefit from surgery Surgery for Epilepsy. Surgical treatment aims to stop seizures by excising or isolating the brain area causing epilepsy. Normal imaging findings do not exclude the possibility of epilepsy surgery.
  • Find out about locally relevant unit(s) that perform assessments for epilepsy surgery.
  • In severe epilepsy, nerve stimulation Deep Brain and Cortical Stimulation for Epilepsy, Transcranial Magnetic Stimulation for the Treatment of Epilepsy and, in special cases, dietary treatment Polyunsaturated Fatty Acid Supplementation for Drug-Resistant Epilepsy can be considered in addition to pharmacotherapy 1.

    References

    • Löscher W, Potschka H, Sisodiya SM et al. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev 2020;72(3):606-638. [PubMed]
    • Brodie MJ. Tolerability and Safety of Commonly Used Antiepileptic Drugs in Adolescents and Adults: A Clinician's Overview. CNS Drugs 2017;31(2):135-147. [PubMed]