Epilepsy: what are the best medications?

In this blog for people making choices about epilepsy medication, Dr Alexandre Mathy, a neurology registrar at Oxford University Hospitals, explains what the latest Cochrane evidence tells us about which medications may be most effective and best tolerated for people with focal seizures or generalised onset tonic‐clonic seizures. 

Take-home points:

Epilepsy is a common neurological condition characterised by recurrent attacks of abnormal brain activity called “seizures” Most people with epilepsy can be successfully treated by taking a single daily anti-epileptic medication A Cochrane Review (published in April 2022) evaluated which anti-epileptic medication options are most effective and best tolerated for the two main types of epilepsy: focal seizures (that start in one area of the brain) and generalised onset tonic‐clonic seizures (that start in both cerebral hemispheres at the same time). This information may help healthcare professionals and people affected by epilepsy make informed decisions when discussing the potential benefits and risks of the various treatment options available.

What is epilepsy?

Despite being common (affecting about 1% of the global population), epilepsy remains a condition shrouded in mystery. The ancients called it the Sacred Disease, as epileptic fits were felt to be due to the Gods taking temporary control of the patient’s body.  We now know that epilepsy is caused by abnormal synchronised activity in the brain causing attacks that we call seizures.

Seizures are short attacks typically lasting minutes.  They can take many forms depending on where in the brain the abnormal activity occurs. A seizure arising from a structure in the brain called the temporal lobe might manifest as the patient experiencing déjà-vu and subtle involuntary movements such as lip smacking, and then losing awareness for a few minutes. These types of seizures that come from a restricted part of the brain are called “focal”.

Seizures affecting the whole brain at once are called “generalised” and will look like the more typical fits seen in Hollywood films, with loss of awareness and violent rhythmic movements of the limbs on both sides of the body.

Seizures can lead to injuries (for instance, fractures sustained during a seizure) and, uncommonly, death (called Sudden Unexplained Death in Epilepsy – SUDEP). They can also impact on patient’s daily life in other ways. For instance because of restrictions placed on their driving or placing limits on the types of work they can do.

How is epilepsy treated?

Fortunately, most people with epilepsy can be rendered completely seizure free with appropriate treatment. For most people, this will be with antiepileptic drugs (AEDs). Indeed, over 50% of people with epilepsy can be seizure-free with a single drug.

The people who still have seizures despite drug treatment may be candidates for epilepsy surgery where the part of the brain causing the seizures is removed by a brain surgeon. The evidence for epilepsy surgery was summarised in a recent Cochrane review Surgery for epilepsy (published June 2019). Other treatment options include vagal nerve stimulation and a special diet called the “ketogenic diet”, which were also the subject of Cochrane Reviews (see Vagus nerve stimulation for partial seizures and Ketogenic diets for drug‐resistant epilepsy respectively).

What drug treatments are the best for treating epilepsy?

There are currently 27 medications licensed to treat epilepsy in the UK. This seems like an embarrassment of riches, but it can be overwhelming both to people and the doctors treating them. How to choose between the treatments?

Fortunately, there is now good evidence to support this decision. A recent Cochrane Review Antiepileptic drug monotherapy for epilepsy: a network meta‐analysis of individual participant data (published April 2022) looked at the clinical trials comparing the 11 most commonly used AEDs and used a sophisticated statistical technique called a “Network Meta-analysis” to summarise this evidence and provide a ranking of the best treatments separately for focal and generalised epilepsy. The trials included adults and children.

defining what the “best treatment” means is not as easy as it sounds: a treatment may be excellent at reducing seizures but cause such intolerable side effects that the patient can’t remain on it for long

Note that defining what the “best treatment” means is not as easy as it sounds: a treatment may be excellent at reducing seizures but cause such intolerable side effects that the patient can’t remain on it for long. Indeed, the review found that the oldest AEDs, phenobarbital and phenytoin, were the most effective at preventing seizures, but were poorly tolerated.

To incorporate side effects, the review ranked the treatments according to “time to treatment failure”, which takes into account whether a patient stopped a treatment due to it not working against the seizures, or stopped it due to side effects. Using this measure, they found reliable evidence that lamotrigine and levetiracetam were the best treatment for focal epilepsy.

For people with generalised epilepsy, there was moderate-certainty evidence for sodium valproate being the best for seizure control, with lamotrigine and levetiracetam in second place. Note however that sodium valproate is associated with a relatively high risk of developmental problems in babies of mothers taking the drug during pregnancy. Therefore women of childbearing ages will usually be recommended one of the alternative drugs.

AEDs vary widely in their side effect profile, but the most commonly reported side effects across all drugs were drowsiness, fatigue, headaches, gastrointestinal disturbances, dizziness, faintness and skin disorders.

What does this mean for people with epilepsy?

The evidence above provides a good starting point to choose a medication for the main types of epilepsy. The drugs mentioned above have therefore been incorporated in the NICE guidelines for epilepsy as first-line choices.

While the initial phase of finding the right treatment can seem laborious and frustrating, it is worth remembering that it is likely to end in a well-tolerated treatment which keeps the person with epilepsy completely free from seizures

However, every person with epilepsy is different, which is why they should be under the care of a neurologist with expertise in treating this condition. It is not just the efficacy of the AED which will inform the choice of treatment. Other factors will be taken into consideration. For example, interactions of the AED with the person’s existing medications or other medical conditions, and the person’s preferences and priorities.

It is not uncommon for people with epilepsy to find they don’t do well on one of the first-line drugs and need to work down the list of other medications.

While this initial phase of finding the right treatment can seem laborious and frustrating, it is worth remembering that it is likely to end in a well-tolerated treatment which keeps the person with epilepsy completely free from seizures and able to reach their full potential.

Resources for people with epilepsy:

References (pdf)

Join in the conversation on Twitter with @CochraneUK or leave a comment on the blog.

Please note, we cannot give specific medical advice and do not publish comments that link to individual pages requesting donations or to commercial sites, or appear to endorse commercial products. We welcome diverse views and encourage discussion but we ask that comments are respectful and reserve the right to not publish any we consider offensive. Cochrane UK does not fact check – or endorse – readers’ comments, including any treatments mentioned.

Alexandre Mathy is employed as a neurology registrar by NHS and has a Wellcome Trust Clinical Research Career Development Fellowship, employed by Oxford University Pharmacology department.



Epilepsy: what are the best medications? by Alexandre Mathy

is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International

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