Epilepsy: Drug Therapy

Therapeutic target

Prevention of epileptic seizures or reduction in the number of seizures.

Therapy recommendations

  • Antiepileptic drugs may be prescribed in adults after a first seizure, especially if risk factors such as EEG abnormalities, a brain lesion (brain change), and other abnormalities on imaging are present. This procedure should be discussed with the patient.
    • Acute symptomatic seizures: a few days (for systemic causes such as hyponatremia/sodium deficiency) or for a few weeks (for causative acute brain disease).
    • Unprovoked seizures and epilepsies: initiation of therapy immediately thereafter if a relevantly increased risk of recurrence (recurrence of the disease) is to be expected (evidence of epilepsy-type potentials in the EEG or evidence of a potentially epileptogenic lesion in the MRI)

    Younger patients also benefit from immediate anticonvulsant therapy if they are at low risk of recurrence after a first seizure.

  • Depending on the presenting form of epilepsy, the following antiepileptic drugs may be used (note possible reduction in contraceptive protection in women-see table below); note further:
  • For GTKA (generalized tonic-clonic seizure; level 1) and SGTKA (status generalized tonic-clonic seizure; levels 1-4), stepwise therapy is given (see below).
  • Status epileticus:
    • Adults: first-line benzodiazepine therapy (phase I; see below for other phases)Note: If benzodiazepines are administered within 10 min of status epilepticus, mortality (death rate) can be significantly reduced (>10 min 11-fold increased mortality risk).If status epilepticus could not be broken by intravenous therapy with a benzodiazepine, patients recovered from their life-threatening crisis with equal frequency and speed when given levetiracetam, fosphenytoin, or valproate.
    • Children: midazolam nasal or buccal; alternative: diazepam rectal (phase I; see below for other phases).
  • Observe the following instructions (see below):
  • Caveat. Approximately 50% of all female epilepsy patients on chronic antiepileptic drug therapy suffer from antiepileptic drug-associated osteopathy (bone disease)!
  • See also under “Further therapy”.

Further notes

  • Benzodiazepines (e.g., midazolam) i.m. can be used to interrupt epileptic seizures more quickly than i.v. injection: the reason is probably that it takes a long time to establish i.v. access in a seizing patient.
  • * Topiramate: Topiramate is almost 3 times more effective than placebo when used in combination with other medications to reduce the number of seizures in drug-resistant focal epilepsy.
  • Cenobamate achieved seizure freedom in about 1 in 5 patients with difficult-to-treat focal seizures. Mode of action: Sodium channel blocker and also affects presynaptic GABA release, thereby increasing the attenuating effect of this neurotransmitter.The U.S. Food and Drug Administration approved this antiepileptic drug in 2019.

Approval status of commonly used antiepileptic drugs in adults (selection)* (according to [current DGN guideline]).

Active ingredient Focal epilepsy Generalized epilepsy Maximum daily dose* *
Monotherapy (MT) Adjunct therapy (ZT) Monotherapy (MT) Adjunct therapy (ZT)
Brivaracetam no yes no no 200 mg
Carbamazepine Yes yes no no 1,600 mg
Eslicarbazepine acetate Yes yes no no 1,600 mg MT / 1,200 mg ZT
Ethosuximide* * * no no yes yes 2,000 mg
Gabapentin yes yes no no 3,600 mg
Lacosamide yes yes no no 600 mg MT / 400 mg ZT
Lamotrigine Yes yes yes yes 600 mg
Levetiracetam yes yes no yes 3,000 mg
Oxcarbazepine Yes yes no no 2,400 mg
Perampanel no yes no yes 12 mg
Topiramate Yes yes yes yes 400 mg
Valproate Yes yes yes yes 2,000 mg
Zonisamide Yes yes no no 500 mg

* For a more comprehensive listing, see Table 5 of the current DGN guideline:* * Maximum recommended daily dose, which may be exceeded in individual cases. * * * The substance is only approved for the treatment of absences. CAVE!Taking valproic acid during pregnancy will harm the child’s intelligence in the long term. The following new agents may be used as add-on therapy for focal and generalized tonic-clonic seizures (see below under “New Agents”):

  • Eslicarbazepine acetate
  • Everolism for seizures in tuberous sclerosis (TSC).
  • Lacosamide for monotherapy in focal seizures.
  • Retigabine

The following new agents may be used as adjunctive therapy for focal seizures with and without generalization (see below under “New Agents”):

  • Perampanel

The following agents may be used for preventive treatment of episodic migraine attacks in adults:

  • Topiramate*
  • Valproate (see below warning: red hand letter).

* Topiramate: Topiramate is nearly 3 times more effective than placebo when used in combination with other medications to reduce the number of seizures in drug-resistant focal epilepsy.

Agents (main indication) in GTKA (generalized tonic-clonic seizure; level 1) and SGTKA (status generalized tonic-clonic seizure; levels 1-4)

Level Agents
1: Seizure and therapy initiation status. Lorazepam
Duration: 5-30 min

Possibly parallel “loading” with stage 2 substances:

  • If cause is not eliminated and / or
  • When sustained anticonvulsant medication must be established
 Diazepam
Clonazepam
Midazolam Clinical seizure control occurs in 76% of cases; this occurs after an average of 41 minutes
2: Benzodiazepine-refractory. Phenytoin Note: Maximum anticonvulsant effect occurs only after 20-30 min (because of limitation of infusion rate).
Duration: 40 min

  • In the absence of seizure control by 1st step resp.
  • In parallel with the establishment of sustained anticonvulsant therapy.
 Valproate Cave.Patients who wish to have children and pregnant women (see below: Notes for “Women with planned pregnancy/when pregnancy has occurred”).
Lacosamide Formally not approved for the treatment of status epilepticus
Levetiracetam
Phenobarbital
3: refractory status Midazolam Note: High rate of accumulation with weaning problems (“weaning”) after prolonged therapy.
Duration: + 60 min: intubation Propofol
Thiopental
4: superrefractory status – ultimate ratio alternatives. Etomidate
Chloral hydrate
Ketamine
Lidocaine
Isoflurane 1 %
Immunomodulation
Ketogenic infusion (fat)
Pyridoxine (vitamin B6)
Hypothermia
CSF-Air Exchange
  • Procedure same for focal seizure or absence status.
  • In refractory status epilepticus (RES), barbiturates are usually used in midazolam failure; 23 hours afterward, a “burst suppression” pattern was achieved on average (note: in burst suppression, brain activity is reduced almost to brain death (ioselectric curve progression)); efficacy was 65%. Subsequently, inhaled anesthetics, ketamine, and hypothermia (hypothermia) were used.
  • The mortality (death rate) of RSE in children is as high as 30%. About 50% of survivors have neurologic deficits.

Further notes

  • In 2015, the European Medicines Agency (EMA) issued a positive opinion on brivaracetam (BRV) as an add-on therapy for patients aged 16 years and older with uncontrolled focal seizures. For methodological reasons, the Institute for Quality and Efficiency in Health Care (IQWiG) sees no evidence of additional benefit for the epilepsy drug brivaracetam (Briviact).
  • A meta-analysis on brivaracetam showed a relative risk of 1.75 for 50% seizure reduction or seizure freedom, which was significantly better than the placebo group (4.74)

Evidence on the influence of antiepileptic drugs on conception protection (ovulation inhibitors; hormone-containing contraceptives)

Decrease in contraceptive protection Possible reduction of contraceptive protection No effect on contraceptive protection(according to studies and professional information)
Carbamazepine Lamotrigine Ethosuximide
Oxcarbazepine Topiramate (400 mg/d in combination with valproate) Gabapentin
Phenobarbital Lacosamide
Phenytoin Levetiracetam (<1,000 mg/d)
Primidone Pregabalin
Perampanel Topiramate (<200 mg)
Eslicarbazepine acetate Zonisamide
Lacosamide

Instructions for women with planned pregnancy/if pregnancy has occurred

  • Initial initiation of valproate should be avoided in women of childbearing potential (because of risk of teratogenicity/misformations)
  • Red Hand Letter (AkdÄ Drug Safety Mail | 38-2014) on valproate: dose-dependent risk of neonatal anomalies; high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases).Valproate should be prescribed to girls, female adolescents, women of childbearing age, or pregnant women only if other drugs are not effective or not tolerated.
  • Physicians and pharmacists are urged to give the patient card to each female patient of childbearing age whenever valproate is prescribed or dispensed and to explain its contents (AkdÄ Drug Safety Mail | 23-2017).
  • Red-hand letter (AkdÄ Drug Safety Mail): contraindications, warnings, and measures to avoid exposure to valproate during pregnancy:
    • In girls and women of childbearing age, valproate should be used only if other treatments are not effective or are not tolerated.
    • Valproate is contraindicated in women of childbearing age unless the pregnancy prevention program is followed.
    • Valproate is contraindicated in epilepsy during pregnancy unless no suitable alternatives are available.
    • Valproate is contraindicated during pregnancy for bipolar disorder and migraine prophylaxis.
  • Before a planned pregnancy: take 1-5 mg folic acid; avoid antiepileptic drug combinations; any epileptic drug should be given at the lowest effective dose; avoid initial exposure to valproate if possible (fetal valproate exposure shows a dose-dependent association with cognitive deficits; see also “Red Hand Letter” above).
  • If pregnancy has occurred: no more major drug changes; 1-5 mg folic acid in the 1st trimester (third trimester); if necessary, attempt to reduce to monotherapy at the lowest effective dose
  • Retigabine should not be used in women of childbearing age.
  • Pregnancies in women who suffer from epilepsy are more likely to have complications, according to a study. The risk of mortality (death) in the delivery room was also significantly increased: 80 maternal deaths per 100,000 pregnancies (normal collective: 6 per 100,000).
  • Women with epilepsy had an increased risk of spontaneous abortion, antepartum and postpartum bleeding complications, and hypertensive crises compared with women without epilepsy.
  • Taking valproic acid during pregnancy harms the child’s intelligence in the long term.

Children with severe, refractory epilepsy

  • The active ingredient cannabidiol (CBD) found in cannabis can reduce seizure frequency by more than 50% in children with severe, treatment-resistant epilepsies (e.g., Dravet syndrome, Lennox-Gastaut syndrome).

Supplements (dietary supplements; vital substances)

The antiepileptic drugs that are used lead to an increased demand for numerous vital substances. Antiepileptic drugs induce cytochrome P450-containing monooxygenases in the liver, which accelerate the degradation and metabolism of vitamin D. This results in a decrease in serum 25-(OH)- and 1,25-(OH)2-vitamin D levels. Long-term ingestion results in vitamin D deficiency. Long-term intake further leads to deficiency of biotin, vitamin A, vitamin B6, vitamin B12. Long-term use of multiple antiepileptic drugs leads to.

  • Low calcium levels in the blood
  • Low L-carnitine values in the blood
  • Low levels of folic acid in the blood (controversial study situations: sometimes a positive effect could be shown by folic acid intake and sometimes it had no effect)

For example, lamotrigine leads to a decrease in plasma osteocalin levels, with the result that

Conclusion: taking vitamin D (400 I.U. ), calcium (500 mg) and vitamin K is advisable.

Suitable dietary supplements should contain the following vital substances:

Note: The listed vital substances are not a substitute for drug therapy. Food supplements are intended to supplement the general diet in the particular life situation.