Withdrawal of antiepileptic drugs in seizure-free adults

Whether or not antiepileptic drugs should be withdrawn after a patient has been seizure-free for several years is a complex issue. Some studies suggest the overall risk of seizure recurrence is approximately 30% if treatment is withdrawn. Clinical factors associated with a greater chance of successful withdrawal include childhood onset epilepsy, a normal electroencephalogram prior to drug withdrawal, being seizure-free for more than two years, monotherapy, normal neuroimaging and normal intellect. If antiepileptic drugs are withdrawn, they should be withdrawn slowly, ideally over several months.

Longitudinal and community-based studies suggest that antiepileptic drugs will result in approximately 70% of adults diagnosed with epilepsy becoming seizure-free.¹ Whether or not antiepileptic drugs should be withdrawn after a patient has been seizure-free for several years is a complex issue. Discontinuing antiepileptic drugs implies the seizure tendency is no longer present. A number of clinical factors can help to predict the risk of seizure recurrence. This can assist when making a decision as to whether or not to discontinue antiepileptic drug treatment. The decision must include weighing up the harms and benefits of continuing and discontinuing therapy, and the risk and consequences of seizure recurrence.

For many adults a recurrence of their seizures would have significant implications. Seizures impact on the ability to drive, possibly the ability to work. For many patients there is a significant negative impact on their psychological state and well-being. Seizures may also be associated with injury, and sudden unexpected death may occur as a direct result of seizures, particularly tonic-clonic seizures. Although the risk of seizure recurrence may be low, some patients choose to remain on treatment as they feel more secure taking an antiepileptic drug.

Patients may want to stop their treatment because antiepileptic drugs are commonly associated with mild adverse effects and have the potential for serious adverse effects. The risk of teratogenicity in women of childbearing years may prompt drug withdrawal earlier than might otherwise occur, but the risk of seizures recurring in pregnancy needs to be balanced against the possible harm of continuing treatment. Other problems include interactions with other drugs, for example the interaction between carbamazepine (liver enzyme inducer) and the oral contraceptive pill. For some patients, taking daily medication is a constant reminder of their chronic condition and has a negative impact on their well-being.

A meta-analysis of 25 studies estimated the overall rate of seizure relapse following the withdrawal of antiepileptic drugs.² After discontinuing therapy 25% of patients relapsed within one year and 29% by two years. A randomised study of continued treatment versus slow withdrawal in 1013 patients who had been seizure-free for at least two years, reported that 78% of patients who continued treatment and 59% of those who stopped treatment were still seizure-free two years later.³ These figures are overall estimates only and several factors need to be considered in individual patients when determining risk of relapse.

A number of studies have assessed clinical factors which might predict seizure recurrence following antiepileptic drug withdrawal (see Table 1).

The risk of seizure recurrence following drug withdrawal is higher in adolescents than children.^2,3 This probably reflects the prognosis of age-related syndromes. Childhood absence epilepsy and benign rolandic epilepsy have a good prognosis for antiepileptic drug withdrawal while juvenile myoclonic epilepsy is more likely to recur.

Epilepsy is not one disease, but comprises a number of syndromes each with a different prognosis (see Box 1). Juvenile myoclonic epilepsy, probably the commonest type of primary generalised epilepsy in adults, has a high risk of seizure recurrence on drug withdrawal.

Studies assessing seizure type report myoclonic seizures, tonic-clonic seizures and partial seizures as associated with an increased risk of seizure recurrence following antiepileptic drug withdrawal.³ One study reported 63% of patients with partial seizures relapsed on drug withdrawal.⁴ Remote symptomatic seizures (defined as seizures occurring in patients with a prior neurologic insult such as head injury, stroke or history of intellectual disability) are associated with a high risk of seizure relapse following discontinuation of therapy.²

The UK Medical Research Council (MRC) trial found that an increased risk of seizure recurrence was associated with:

• a shorter duration of seizure-free period prior to study entry
• seizures after starting antiepileptic drug treatment
• patients taking multiple antiepileptic drugs at the time of study entry.³

There is limited evidence to support the assumption that an interictal electroencephalogram (EEG) is predictive of seizure recurrence following antiepileptic drug withdrawal. The MRC study found that patients with only tonic-clonic seizures and generalised spike wave on EEG had a higher recurrence rate. Patients with tonic-clonic seizures and focal features or normal EEG had no increased risk of recurrence.³

The meta-analysis of 25 studies noted that an abnormal EEG was associated with an increased risk of recurrence, but there was considerable variability in the results and in most studies the epileptiform activity was not differentiated.² In some studies patients with an abnormal EEG, particularly the presence of epileptiform activity, were excluded, biasing the results.

Another study assessed the role of the EEG in predicting seizure recurrence in partial epilepsies. It found that although the interictal EEG at time of antiepileptic drug withdrawal did not predict recurrence, a worsening of the EEG after withdrawal was predictive of seizure recurrence.⁴

Role of video-EEG monitoring

The value of video-EEG monitoring in assessing the chance of remaining seizure-free following antiepileptic drug withdrawal has not been systematically studied. However, it is not uncommon for patients with generalised epilepsy to report no seizures and yet continuous monitoring reveals frequent sub-clinical seizure activity.

Although studies are lacking, it seems likely that patients with an epileptogenic lesion on computed tomography or magnetic resonance imaging of the brain are more likely to have recurrences on drug withdrawal. This is consistent with the data on recurrences in a population of patients presenting with their first seizure - patients with an epileptogenic lesion on neuroimaging have a higher risk of seizure recurrence.⁵

It is likely that provoked seizures (such as seizures occurring with excess alcohol, sleep deprivation or induced by drugs) are less likely to recur if these factors are avoided.

Occasionally patients are commenced on an antiepileptic drug and in retrospect there is some doubt about the diagnosis of epilepsy. In these patients drug withdrawal is a reasonable option.

A reduction in antiepileptic drug therapy following successful surgery on the temporal lobe should be considered. However, the timing of withdrawal and whether or not all medications should be withdrawn is controversial. Many experts would agree that treatment should continue for two years. If the patient is then seizure-free and on several drugs, a reduction in medication could be commenced, but at least one antiepileptic drug should be continued for the long term.⁶

No randomised-controlled trials have studied how long patients should be seizure-free before withdrawing their treatment can be considered. Studies in children suggest two years, but the MRC study of adults suggests a longer period of at least three years is desirable.³

Patients need to be advised there is no guarantee they will remain seizure-free. The risk of relapse is greatest during the first 12 months.

'Assessing fitness to drive', produced by Austroads and the National Road Transport Commission, advises that the patient 'should not drive for the full period of withdrawal and for three months thereafter' unless withdrawal is advised by an experienced consultant on the basis that the risk of seizure recurrence is low.⁷ Safety advice such as not swimming alone, avoiding heights and having a shower rather than a bath, should be reinforced.

Withdrawal should be gradual and take place over approximately six months. Rapid withdrawal, particularly of barbiturates and benzodiazepines, can precipitate seizures. The withdrawal protocol for adults in the MRC study decreased doses every four weeks (see Box 2).³ This approach may need to be modified in patients on low doses of antiepileptic drugs. For patients taking multiple drugs, the withdrawal should be sequential.³

If seizures recur the previous medication that controlled seizure should be restarted.

For adults who are seizure-free, there are limited data to help them make an informed decision regarding drug withdrawal. The decision is an individual one and in general should be patient driven, as it is very important that the patient supports the decision, is aware that seizures may recur and understands the associated risks.