21st June 2023

Treatment of epilepsy

63.7% of patients with newly diagnosed epilepsy will become seizure-free within the first year. 86.6% of these patients gained seizure control with a single anti-epileptic drug (AED).

Some antiepileptics are inducers of the cytochrome P450 enzyme, which can increase the metabolism (and therefore alter effectiveness) of certain drugs, such as warfarin and the oral contraceptive pill. This should be taken into consideration when choosing an AED.

Treatment for each seizure type

Absence Seizures

NICE advises the following treatment for absence seizures:

Focal seizures

NICE advises the following treatment for focal seizures:

Generalised Tonic-Clonic Seizures

NICE advises the following treatment for generalised tonic-clonic seizures:

Myoclonic seizures

NICE advises the following treatment for myoclonic seizures:

Status Epilepticus

It is essential that status epilepticus is recognised and treated quickly. Initial management in a healthcare setting should include the following:

• A – secure airway
• B – give high-flow oxygen and assess respiratory function
• C – assess cardiac function and secure IV access with a cannula in a large vein.
• D – check blood glucose levels

Pharmacological management in the community:

• Buccal midazolam 10mg
• Rectal diazepam at 10-20mg

Another dose can be given after 15 minutes.

Pharmacological management in hospital:

• First line treatment – IV lorazepam 0.1 mg/kg. Repeat after 10-20 minutes.
• Second line – IV diazepam.

If no IV access – buccal midazolam.

If seizures continue, IV phenytoin can be used, and in refractory cases, intensive care will likely be required for treatment with propofol or thiopental sodium.

Side Effects

Cytochrome P450 Enzyme

Cytochrome P (CYP) enzymes are haemoproteins that are key in drug metabolism. AEDs are known to either induce or inhibit Cytochrome P450. When a medication induces cytochrome P450, there is an increase in the metabolisation of the medication, which means the medication has less of an effect. When a medication inhibits cytochrome P450, there is reduced metabolisation of the medication and an increased risk of toxicity. Dose of these AEDs might have to be titrated accordingly.

Sodium valproate

Sodium valproate works by increasing GABA activity by decreasing its degradation and by blocking sodium, potassium, and calcium channels.

The severe side effects of sodium valproate, according to the British National Formulary (BNF), include teratogenicity, agranulocytosis, rhabdomyolysis, systemic lupus erythematosus (SLE), and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome, DRESS syndrome, Toxic Epidermal Necrolysis.

Levetiracetam

The mechanism of action of levetiracetam has not been fully elucidated. So far, it has been found that it inhibits presynaptic calcium channels.

The severe side effects of levetiracetam include psychosis, suicidality agranulocytosis, and severe cutaneous adverse reactions.

Lamotrigine

Lamotrigine acts by inhibiting sodium channels and inhibits glutamate release.

The severe side effects of lamotrigine include suicidality, disseminated intravascular coagulation, haemolytic anaemia, and severe cutaneous adverse reactions.

Ethosuximide

Ethosuximide works by inhibiting T-type calcium channels that act in the hyperactive thalamocortical neuronal circuit.

The severe side effects of ethosuximide include suicidality, agranulocytosis, cytopaenia, SLE, and severe cutaneous skin reactions.

Topiramate

Topiramate acts on multiple targets. It acts on voltage-gated sodium channels, voltage-gated calcium channels, GABA receptors, and AMPA glutamate receptors.

The severe side effects of topiramate include facial oedema, glaucoma, neutropaenia severe cutaneous adverse reactions.

Phenytoin

Phenytoin is a voltage-gated sodium channel blocker.

The severe side effects of phenytoin include teratogenicity, agranulocytosis, pancytopaenia, SLE, and severe cutaneous adverse reactions.

Phenytoin toxicity can present with nystagmus, diplopia, slurred speech, ataxia, confusion, and hyperglycaemia.

The signs and symptoms of chronic phenytoin use are hirsutism, acne, coarsening of the facial features, gingival hyperplasia, and megaloblastic anaemia

Clobazam

Clobazam is a benzodiazepine that works by being a partial agonist of GABA-A receptors.

The severe side effects of clobazam include respiratory depression, drowsiness, ataxia, nystagmus, and coma.

DVLA Guidance

Be aware of the Driver and Vehicle Licensing Agency (DVLA) guidance, as patients must be informed of any driving restrictions.

The DVLA guidance for Group 1 licences (cars and motorcycles) for seizures or epilepsy are:

• First unprovoked epileptic seizure or a single isolated seizure – must not drive for 6 months.
• Established epilepsy – must be seizure-free for at least 1 year and have no history of unprovoked seizures.

Contraception

AEDs can affect the effectiveness of contraception or vice versa, so women with epilepsy should be counselled regarding this when prescribing AEDs and/or contraception.

Enzyme-inducing AEDs (see the subsection on Cytochrome P450 under Side Effects) and contraception:

Lamotrigine and contraception:

If a woman with epilepsy plans to get pregnant, she should be referred to an epilepsy specialist for pre-conception counselling and remain on contraception until she has seen that specialist. NICE recommends starting all these women on high dose (5mg) folic acid.

Pregnancy

In those with epilepsy who are pregnant, there is a huge and understandable concern about AEDs harming the unborn baby. Therefore, it is essential to be aware of the potential harms and the rates of harmful effects for each of the common AEDs, so one can counsel a woman on the risks and come to a joint decision on which AED to prescribe. A change in AED might need to be made. Overall, it is essential to emphasise the importance of compliance during pregnancy, as the risk of harm to baby from an epileptic seizure is more likely than the risk of harm from taking the AED.
The Medicines and Healthcare products Regulatory Agency has produced updated advice on AEDs in pregnancy following a comprehensive safety review based on all evidence of the effects of AEDs on the mother and the baby.

The following AEDs have evidence-based harmful effects according to the table below. If the AED is not listed in the table, then either the evidence shows the AED does not increase the risk of the harmful effect, or there is not enough evidence to draw a conclusion either way.

The table below summarises the effect of pregnancy on serum levels of the AED according to studies.