Epilepsy (generalised)

Abstract

Introduction

About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant generalised epilepsy? What are the effects of surgery in people with drug-resistant generalised epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found eight systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: monotherapy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs (lamotrigine or levetiracetam) for drug-resistant epilepsy; and hemispherectomy for drug-resistant epilepsy.

Key Points

During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission.

Carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, and topiramate are widely considered effective in controlling seizures in newly diagnosed generalised (tonic clonic) epilepsy, but we found no RCTs comparing them with placebo, and a placebo-controlled trial would now be considered unethical.

• Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs; we don't know if any one antiepileptic drug is more likely to reduce seizures compared with the others.

Adding second-line drugs to usual treatment reduces seizure frequency in people with drug-resistant generalised epilepsy.

We don't know whether hemispherectomy improves seizure control in people with drug-resistant epilepsy.

About this condition

Definition

Epilepsy is a group of disorders rather than a single disease. Seizures can be classified by type as generalised (categorised as generalised tonic clonic, absence, myoclonic, tonic, and atonic seizures) or partial or focal (categorised as simple partial, complex partial, and secondary generalised tonic clonic seizures). A person is considered to have epilepsy if they have had two or more unprovoked seizures. This review deals with pharmacological and surgical treatments of generalised epilepsy only. For information on drug withdrawal and relapse in undefined epilepsy type (generalised or partial), behavioural and psychological treatments of undefined epilepsy type, and pharmacological treatment of a single seizure that may progress to epilepsy, or pharmacological or surgical treatments of partial epilepsy see review on Epilepsy (partial). Status epilepticus is not covered in this review.

Incidence/ Prevalence

Epilepsy (generalised or partial) is common, with an estimated average prevalence of 5.5/1000 people in Europe, 6.8/1000 people in the United States and 7.5/1000 people in Australia. Prevalence rates in developing countries vary widely, with studies carried in sub-Saharan Africa reporting rates of 5.2 to 74.4/1000 people, studies in Asia reporting overall prevalence rates of 1.5 to 14.0/1000 people, and Latin America reporting rates of 17 to 22/1000 people. The annual incidence rates of epilepsy are 24 to 56/100,000 people in Europe, 44/100,000 in the United States, 63 to 158/100,000 people in sub-Saharan Africa, 113 to 190/100,000 people in Latin America, and 28.1 to 60/100,000 people in Asia. The worldwide incidence of single unprovoked seizures is 23 to 61/100,000 person-years. About 3% of people will be diagnosed with epilepsy at some time in their lives.

Aetiology/ Risk factors

Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving the brain. The causes/risk factors include birth/neonatal injuries, congenital or metabolic disorders, head injuries, tumours, infections of the brain or meninges, genetic defects, degenerative disease of the brain, cerebrovascular disease, or demyelinating disease. Epilepsy can be classified by cause. Idiopathic generalised epilepsies (such as juvenile myoclonic epilepsy or childhood absence epilepsy) are largely genetic. Symptomatic generalised epilepsies (such as West syndrome and Lennox–Gastaut) are associated with diffuse cerebral dysfunction and may be caused by anoxic brain injury or metabolic defect. Cryptogenic epilepsies are those that cannot be classified as idiopathic or symptomatic.

Prognosis

About 60% of untreated people have no further seizures during the 2 years after their first seizure. Prognosis is good for most people with epilepsy. About 70% go into remission, defined as being seizure free for 5 years on or off treatment. This leaves 20% to 30% who develop chronic epilepsy, which is often treated with multiple antiepileptic drugs.

Aims of intervention

To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; to improve quality of life; in people in remission, to withdraw antiepileptic drugs without causing seizure recurrence; to minimise adverse effects of treatment.

Outcomes

For treatment of newly diagnosed epilepsy: Time to remission, time to first seizure after treatment, retention on allocated treatment or time to withdrawal of allocated treatment. For treatment of drug-resistant epilepsy: Percentage reduction in seizure frequency, proportion of responders (response defined as at least 50% reduction in seizure frequency). For all: quality of life, adverse effects.

Methods

Clinical Evidence search and appraisal July 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2009, Embase 1980 to July 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 2 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least double-blinded for drug trials, and containing more than 20 individuals of whom more than 80% were followed up. At least 3 months' follow-up was required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We aimed to include studies in people with generalised epilepsy or where a subgroup analysis was carried out in people with generalised epilepsy. However, where studies included a mixture of partial and generalised epilepsy, we included studies in which at least 60% of people had generalised epilepsy. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratio (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for Epilepsy (generalised)

Important outcomes	Seizure frequency, quality of life, adverse effects
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)?
4 (395)	Seizure frequency	Carbamazepine v sodium valproate	4	−1	0	−1	0	Low	Quality point deducted for subgroup analysis. Directness point deducted for uncertainty about epilepsy classification
4 (157)	Seizure frequency	Carbamazepine v phenobarbital	4	−2	0	0	0	Low	Quality points deducted for sparse data and for subgroup analysis
5 (395)	Seizure frequency	Phenytoin v sodium valproate	4	−1	0	0	0	Moderate	Quality point deducted for subgroup analysis
2 (147)	Seizure frequency	Phenytoin v oxcarbazepine	4	−2	0	0	0	Low	Quality points deducted for sparse data and subgroup analysis
1 (186)	Seizure frequency	Lamotrigine v carbamazepine controlled release	4	−1	0	−2	0	Very low	Quality point deducted for sparse data. Directness points deducted for uncertainty about epilepsy type and population restricted to older people
What are the effects of additional treatments in people with drug-resistant generalised epilepsy?
1 (26)	Seizure frequency	Adding lamotrigine v adding placebo	4	−2	0	0	0	Low	Quality point deducted for sparse data and no pre-crossover results
2 (286)	Seizure frequency	Adding levetiracetam v adding placebo	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting in one RCT

Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Absence seizure

Previously known as “petit mal”. Brief episodes of unconsciousness with vacant staring, sometimes with fluttering of the eyelids, as if “daydreaming”. People with absence seizure do not fall to the ground and generally have a rapid recovery. The condition is rare in adults.

Atonic seizure

Momentary loss of limb muscle tone causing sudden falling to the ground or drooping of the head.

Hemispherectomy

is a surgical procedure in which a large part of a cerebral hemisphere (diseased) is removed. This procedure has recently been modified so that one side of the brain (that is, one cerebral hemisphere) is disconnected from the rest of the brain. This is called “functional hemispherectomy”.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Tonic clonic seizure

Also known as a convulsion or “grand mal” attack. The person will become stiff (tonic) and collapse, and have generalised jerking (clonic) movements. Breathing might stop and the bladder might empty. Generalised jerking movements lasting typically for a few minutes are followed by relaxation and deep unconsciousness, before the person slowly comes round. People are often tired and confused, and may remember nothing. Tonic clonic seizures may follow simple partial or complex partial seizures (see above), where they are classified as secondary generalised tonic clonic seizures. Tonic clonic seizures occurring without warning and in the context of generalised epilepsy are classified as generalised tonic clonic seizures.

Very low-quality evidence

Any estimate of effect is very uncertain.

Pharmacological and surgical treatments of partial epilepsy; drug withdrawal and relapse in undefined epilepsy type; behavioural and psychological treatments of undefined epilepsy type; and pharmacological treatment of a single seizure that may progress to epilepsy, see review on Epilepsy (partial). Treatment of typical absence seizures in children, see review on Absence seizures in children.

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