Epilepsy (generalised seizures) Search date April 2014 J. Helen Cross 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 question: What are the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (BMJ 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 four 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 on the addition of the following interventions: lacosamide, lamotrigine, levetiracetam, perampanel, and zonisamide versus the addition of placebo.
QUESTIONS What are the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS TREATING DRUG-RESISTANT EPILEPSY (GENERALISED SEIZURES) Likely to be beneficial Addition of lamotrigine compared with adding placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . . . . . . . . . 3 Addition of levetiracetam compared with addition of placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . 5 Unknown effectiveness
Addition of perampanel compared with the addition of placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . 6 Addition of zonisamide compared with the addition of placebo in people with drug-resistant epilepsy characterised by generalised seizure New . . . . . . . . . . . . 7 Covered elsewhere in Clinical Evidence Treatment of typical absence seizures in children, see review on Absence seizures in children. To be covered in future updates
Addition of lacosamide compared with adding placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . . . . . . . . . 3
Topiramate Rufinamide Clobazam
Key points • Epilepsy is a group of disorders rather than a single disease. • Seizures can be classified as generalised or focal. This review examines the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures. • During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission. • Adding lamotrigine seems to be more effective than adding placebo at reducing seizure frequency in people with drug-resistant epilepsy characterised by generalised seizures. • Adding levetiracetam seems to be more effective than adding placebo at reducing seizure frequency in people with drug-resistant epilepsy characterised by generalised seizures. • The RCTs we found were relatively short term (12–24 weeks) and we found no longer term studies. There is a need for further long-term studies to confirm the ongoing efficacy and safety of agents. • We don’t know about the benefits of adding lacosamide, perampanel, or zonisamide compared to adding placebo, as we found no systematic reviews or RCTs. Clinical context DEFINITION
Epilepsy is a group of disorders rather than a single disease. Seizures can be classified by type as generalised (generalised tonic clonic, absence, myoclonic, tonic, and atonic seizures) or focal (previously categorised as simple partial, complex partial, and secondary generalised tonic clonic [1] seizures). A person is considered to have epilepsy if he/she has had two or more unprovoked
© BMJ Publishing Group Ltd 2015. All rights reserved.
.................... 1 ....................
Clinical Evidence 2015;04:1201
Neurological disorders
..................................................
[2]
seizures or has had a single seizure and is regarded as at significant risk of a second. When a diagnosis of epilepsy has been made, the epilepsy syndrome should be characterised if possible, dependent on the electroclinical features (e.g., childhood absence epilepsy is characterised by age of onset [5-10 years], frequent short absence seizures, and an EEG demonstrating 3 Hz spike and wave). The optimal first-line medication will be chosen, dependent on the syndrome; the intervention most likely to lead to benefit and least likely to cause aggravation of seizures. Valproate remains the most effective medication as first-line treatment in many of the epilepsies characterised by predominantly generalised seizures (e.g., genetic generalised epilepsy), especially those including [3] generalised tonic clonic seizures. Ethosuximide may be the first drug of choice in generalised [4] epilepsies characterised by absence seizures. Side effects of medication also need to be kept to a minimum. There has been emerging concern about the effect of valproate on the unborn child, specifically with regard to postnatal neurocognitive development. Consequently it is now not considered as treatment of choice in women of child bearing age. This has led to wider use of levetiracetam and lamotrigine as alternative first line treatment in this population. This review deals with additional pharmacological treatments for people with drug-resistant epilepsy characterised by generalised seizures. Status epilepticus is not covered in this review. INCIDENCE/ PREVALENCE
[5]
Epilepsy is common, with an estimated average prevalence of 5.5/1000 people in Europe, [6] 6.8/1000 people in the US, and 7.5/1000 people in Australia. Prevalence rates in developing countries vary widely, with studies carried out in sub-Saharan Africa reporting rates of 5.2 to [7] 74.4/1000 people, studies in Asia reporting overall prevalence rates of 1.5 to 14.0/1000 people, [8] [9] and Latin America reporting rates of 17 to 22/1000 people. The worldwide incidence of epilepsy (defined as 2 or more unprovoked seizures occurring at least 24 hours apart) is 50.4/100,000 people per year.The incidence is approximately 45.0/100,000 per year for high-income [10] countries and 81.7/100,000 per year for low- and middle-income countries. The worldwide inci[11] dence of single unprovoked seizures is 23 to 61/100,000 person-years. About 3% of people [12] will be diagnosed with epilepsy at some time in their lives.
AETIOLOGY/ Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving RISK FACTORS the brain. Where possible, an epilepsy will be described as an electroclinical syndrome. The causes/risk factors, however, remain wide and include birth/neonatal injuries, congenital or metabolic disorders, head injuries, tumours, infections of the brain or meninges, genetic defects, malformations of the brain, degenerative disease of the brain, cerebrovascular disease, or demyeli[1] nating disease; these may be grouped as genetic, structural/metabolic, or unknown. PROGNOSIS
After their first seizure, about 60% of untreated people have no further seizures in the following 2 [13] years. 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 continue to have epileptic seizures, despite treatment with anti-epileptic drugs. This group are often treated with [14] multiple anti-epileptic drugs.
AIMS OF To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; INTERVENTION to improve quality of life; to minimise adverse effects of treatment. OUTCOMES
Seizure frequency percentage reduction in seizure frequency, proportion of responders (response defined as at least 50% reduction in seizure frequency); quality of life; adverse effects.
METHODS
BMJ Clinical Evidence search and appraisal April 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2014, Embase 1980 to April 2014, and The Cochrane Database of Systematic Reviews 2014, issue 4 (1966 to date of issue). Additional searches were carried out in the the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least doubleblinded and containing at least 20 individuals (at least 10 per arm), of whom at least 80% were followed up. There was a minimum length of follow-up of 3 months. 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 seizures (excluding status epilepticus) 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 epileptic seizures. We included RCTs and systematic reviews of RCTs where
© BMJ Publishing Group Ltd 2015. All rights reserved.
........................................................... 2
Neurological disorders
Epilepsy (generalised seizures)
harms of an included intervention were assessed, 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 FDA and the 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 ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 9 ). The categorisation of the quality of the evidence (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 BMJ 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). QUESTION
What are the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures?
OPTION
ADDITION OF LACOSAMIDE COMPARED WITH ADDING PLACEBO IN PEOPLE WITH DRUGRESISTANT EPILEPSY CHARACTERISED BY GENERALISED SEIZURES. . . . . . . . . . . New
We found no direct information from RCTs about whether the addition of lacosamide is better than placebo in people with drug-resistant epilepsy characterised by generalised seizures. For GRADE evaluation of interventions for epilepsy, see table, p 9 . Benefits:
Adding lacosamide versus adding placebo: We found no systematic review or RCTs.
Harms:
Antiepileptic drugs have been associated with an increased risk of suicidal behaviour and ideation. [15]
See Comment section for further information on potential harms of anti-epileptics, p 3 . Adding lacosamide versus adding placebo: We found no RCTs. Comment:
Lacosamide is increasingly used as add-on therapy where other medication has failed. There is little evidence to suggest the medication is problematic; in particular, there is little evidence of aggravation of seizures. Some anti-epileptic drugs (AEDs) are associate with an increased risk for congenital malformations [16] in the unborn child in women taking AEDs while pregnant. There has been increasing concern about the effects of valproate on longer term cognition and behaviour in children born to mothers [17] [18] [19] [20] taking valproate during pregnancy. There is no data available on teratogenic effects for lacosamide. Clinical guide Lacosamide is available to be used as an add-on agent where existing anti-epileptic drugs have failed. Individuals initiated on this medication should be under on-going review by an epilepsy specialist.
OPTION
ADDITION OF LAMOTRIGINE COMPARED WITH ADDING PLACEBO IN PEOPLE WITH DRUGRESISTANT EPILEPSY CHARACTERISED BY GENERALISED SEIZURES. . . . . . . . . . . New
Seizure frequency Adding lamotrigine compared with adding placebo Adding lamotrigine seems more effective than adding placebo at decreasing the frequency of generalised tonic clonic seizures and at increasing the proportion of people with a 50% or greater reduction in generalised seizures (moderate-quality evidence). For GRADE evaluation of interventions for epilepsy, see table, p 9 . Benefits:
Adding lamotrigine versus adding placebo: [21] [22] We found one systematic review and one subsequent RCT comparing addition of lamotrigine with addition of placebo in people who had not responded to usual drug treatment.
© BMJ Publishing Group Ltd 2015. All rights reserved.
...........................................................
3
Neurological disorders
Epilepsy (generalised seizures)
The systematic review (search date 2010, 2 RCTs, 143 people, aged 2–55 years, 51% men) compared the addition of lamotrigine with placebo in people with generalised tonic clonic seizures with or without other generalised seizure types (e.g., absence or myoclonic seizures). The review did not pool the data due to differences in study design between the two RCTs (one was a crossover [21] RCT and the other a parallel RCT). The first RCT (crossover design, 26 people with absence, myoclonic, or generalised tonic clonic seizures or a combination of these [excluding Lennox-Gastaut epilepsy], aged 15–50 years [mean age 29 years], 42% male) compared adding lamotrigine (75 mg or 150 mg once-daily) with adding placebo to usual drug treatment (up to 4 drugs allowed, including valproate [26 people], carbamazepine [11 people], clonazepam [5 people], phenytoin [3 [23] people], ethosuximide [2 people], primidone [2 people]). The RCT reported results after crossover and separately by seizure type. It found that, in people with generalised tonic clonic or absence seizures, adding lamotrigine significantly increased the proportion of people with a 50% or greater reduction in seizure rate (percentage reduction in seizure rate calculated from the individual seizure rate in the adjunctive-lamotrigine treatment phase compared with the seizure rate in the adjunctive placebo phase) after 12 weeks’ treatment (proportion of people with at least a 50% reduction in seizure rate: generalised seizures: 7/14 [50%], P = 0.03; absence seizures: 5/15 [33%], P
QUESTIONS What are the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS TREATING DRUG-RESISTANT EPILEPSY (GENERALISED SEIZURES) Likely to be beneficial Addition of lamotrigine compared with adding placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . . . . . . . . . 3 Addition of levetiracetam compared with addition of placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . 5 Unknown effectiveness
Addition of perampanel compared with the addition of placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . 6 Addition of zonisamide compared with the addition of placebo in people with drug-resistant epilepsy characterised by generalised seizure New . . . . . . . . . . . . 7 Covered elsewhere in Clinical Evidence Treatment of typical absence seizures in children, see review on Absence seizures in children. To be covered in future updates
Addition of lacosamide compared with adding placebo in people with drug-resistant epilepsy characterised by generalised seizures New . . . . . . . . . . . . . . . . . . . . 3
Topiramate Rufinamide Clobazam
Key points • Epilepsy is a group of disorders rather than a single disease. • Seizures can be classified as generalised or focal. This review examines the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures. • During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission. • Adding lamotrigine seems to be more effective than adding placebo at reducing seizure frequency in people with drug-resistant epilepsy characterised by generalised seizures. • Adding levetiracetam seems to be more effective than adding placebo at reducing seizure frequency in people with drug-resistant epilepsy characterised by generalised seizures. • The RCTs we found were relatively short term (12–24 weeks) and we found no longer term studies. There is a need for further long-term studies to confirm the ongoing efficacy and safety of agents. • We don’t know about the benefits of adding lacosamide, perampanel, or zonisamide compared to adding placebo, as we found no systematic reviews or RCTs. Clinical context DEFINITION
Epilepsy is a group of disorders rather than a single disease. Seizures can be classified by type as generalised (generalised tonic clonic, absence, myoclonic, tonic, and atonic seizures) or focal (previously categorised as simple partial, complex partial, and secondary generalised tonic clonic [1] seizures). A person is considered to have epilepsy if he/she has had two or more unprovoked
© BMJ Publishing Group Ltd 2015. All rights reserved.
.................... 1 ....................
Clinical Evidence 2015;04:1201
Neurological disorders
..................................................
[2]
seizures or has had a single seizure and is regarded as at significant risk of a second. When a diagnosis of epilepsy has been made, the epilepsy syndrome should be characterised if possible, dependent on the electroclinical features (e.g., childhood absence epilepsy is characterised by age of onset [5-10 years], frequent short absence seizures, and an EEG demonstrating 3 Hz spike and wave). The optimal first-line medication will be chosen, dependent on the syndrome; the intervention most likely to lead to benefit and least likely to cause aggravation of seizures. Valproate remains the most effective medication as first-line treatment in many of the epilepsies characterised by predominantly generalised seizures (e.g., genetic generalised epilepsy), especially those including [3] generalised tonic clonic seizures. Ethosuximide may be the first drug of choice in generalised [4] epilepsies characterised by absence seizures. Side effects of medication also need to be kept to a minimum. There has been emerging concern about the effect of valproate on the unborn child, specifically with regard to postnatal neurocognitive development. Consequently it is now not considered as treatment of choice in women of child bearing age. This has led to wider use of levetiracetam and lamotrigine as alternative first line treatment in this population. This review deals with additional pharmacological treatments for people with drug-resistant epilepsy characterised by generalised seizures. Status epilepticus is not covered in this review. INCIDENCE/ PREVALENCE
[5]
Epilepsy is common, with an estimated average prevalence of 5.5/1000 people in Europe, [6] 6.8/1000 people in the US, and 7.5/1000 people in Australia. Prevalence rates in developing countries vary widely, with studies carried out in sub-Saharan Africa reporting rates of 5.2 to [7] 74.4/1000 people, studies in Asia reporting overall prevalence rates of 1.5 to 14.0/1000 people, [8] [9] and Latin America reporting rates of 17 to 22/1000 people. The worldwide incidence of epilepsy (defined as 2 or more unprovoked seizures occurring at least 24 hours apart) is 50.4/100,000 people per year.The incidence is approximately 45.0/100,000 per year for high-income [10] countries and 81.7/100,000 per year for low- and middle-income countries. The worldwide inci[11] dence of single unprovoked seizures is 23 to 61/100,000 person-years. About 3% of people [12] will be diagnosed with epilepsy at some time in their lives.
AETIOLOGY/ Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving RISK FACTORS the brain. Where possible, an epilepsy will be described as an electroclinical syndrome. The causes/risk factors, however, remain wide and include birth/neonatal injuries, congenital or metabolic disorders, head injuries, tumours, infections of the brain or meninges, genetic defects, malformations of the brain, degenerative disease of the brain, cerebrovascular disease, or demyeli[1] nating disease; these may be grouped as genetic, structural/metabolic, or unknown. PROGNOSIS
After their first seizure, about 60% of untreated people have no further seizures in the following 2 [13] years. 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 continue to have epileptic seizures, despite treatment with anti-epileptic drugs. This group are often treated with [14] multiple anti-epileptic drugs.
AIMS OF To reduce the risk of subsequent seizures and to improve the prognosis of the seizure disorder; INTERVENTION to improve quality of life; to minimise adverse effects of treatment. OUTCOMES
Seizure frequency percentage reduction in seizure frequency, proportion of responders (response defined as at least 50% reduction in seizure frequency); quality of life; adverse effects.
METHODS
BMJ Clinical Evidence search and appraisal April 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2014, Embase 1980 to April 2014, and The Cochrane Database of Systematic Reviews 2014, issue 4 (1966 to date of issue). Additional searches were carried out in the the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least doubleblinded and containing at least 20 individuals (at least 10 per arm), of whom at least 80% were followed up. There was a minimum length of follow-up of 3 months. 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 seizures (excluding status epilepticus) 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 epileptic seizures. We included RCTs and systematic reviews of RCTs where
© BMJ Publishing Group Ltd 2015. All rights reserved.
........................................................... 2
Neurological disorders
Epilepsy (generalised seizures)
harms of an included intervention were assessed, 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 FDA and the 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 ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 9 ). The categorisation of the quality of the evidence (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 BMJ 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). QUESTION
What are the effects of additional treatments in people with drug-resistant epilepsy characterised by generalised seizures?
OPTION
ADDITION OF LACOSAMIDE COMPARED WITH ADDING PLACEBO IN PEOPLE WITH DRUGRESISTANT EPILEPSY CHARACTERISED BY GENERALISED SEIZURES. . . . . . . . . . . New
We found no direct information from RCTs about whether the addition of lacosamide is better than placebo in people with drug-resistant epilepsy characterised by generalised seizures. For GRADE evaluation of interventions for epilepsy, see table, p 9 . Benefits:
Adding lacosamide versus adding placebo: We found no systematic review or RCTs.
Harms:
Antiepileptic drugs have been associated with an increased risk of suicidal behaviour and ideation. [15]
See Comment section for further information on potential harms of anti-epileptics, p 3 . Adding lacosamide versus adding placebo: We found no RCTs. Comment:
Lacosamide is increasingly used as add-on therapy where other medication has failed. There is little evidence to suggest the medication is problematic; in particular, there is little evidence of aggravation of seizures. Some anti-epileptic drugs (AEDs) are associate with an increased risk for congenital malformations [16] in the unborn child in women taking AEDs while pregnant. There has been increasing concern about the effects of valproate on longer term cognition and behaviour in children born to mothers [17] [18] [19] [20] taking valproate during pregnancy. There is no data available on teratogenic effects for lacosamide. Clinical guide Lacosamide is available to be used as an add-on agent where existing anti-epileptic drugs have failed. Individuals initiated on this medication should be under on-going review by an epilepsy specialist.
OPTION
ADDITION OF LAMOTRIGINE COMPARED WITH ADDING PLACEBO IN PEOPLE WITH DRUGRESISTANT EPILEPSY CHARACTERISED BY GENERALISED SEIZURES. . . . . . . . . . . New
Seizure frequency Adding lamotrigine compared with adding placebo Adding lamotrigine seems more effective than adding placebo at decreasing the frequency of generalised tonic clonic seizures and at increasing the proportion of people with a 50% or greater reduction in generalised seizures (moderate-quality evidence). For GRADE evaluation of interventions for epilepsy, see table, p 9 . Benefits:
Adding lamotrigine versus adding placebo: [21] [22] We found one systematic review and one subsequent RCT comparing addition of lamotrigine with addition of placebo in people who had not responded to usual drug treatment.
© BMJ Publishing Group Ltd 2015. All rights reserved.
...........................................................
3
Neurological disorders
Epilepsy (generalised seizures)
The systematic review (search date 2010, 2 RCTs, 143 people, aged 2–55 years, 51% men) compared the addition of lamotrigine with placebo in people with generalised tonic clonic seizures with or without other generalised seizure types (e.g., absence or myoclonic seizures). The review did not pool the data due to differences in study design between the two RCTs (one was a crossover [21] RCT and the other a parallel RCT). The first RCT (crossover design, 26 people with absence, myoclonic, or generalised tonic clonic seizures or a combination of these [excluding Lennox-Gastaut epilepsy], aged 15–50 years [mean age 29 years], 42% male) compared adding lamotrigine (75 mg or 150 mg once-daily) with adding placebo to usual drug treatment (up to 4 drugs allowed, including valproate [26 people], carbamazepine [11 people], clonazepam [5 people], phenytoin [3 [23] people], ethosuximide [2 people], primidone [2 people]). The RCT reported results after crossover and separately by seizure type. It found that, in people with generalised tonic clonic or absence seizures, adding lamotrigine significantly increased the proportion of people with a 50% or greater reduction in seizure rate (percentage reduction in seizure rate calculated from the individual seizure rate in the adjunctive-lamotrigine treatment phase compared with the seizure rate in the adjunctive placebo phase) after 12 weeks’ treatment (proportion of people with at least a 50% reduction in seizure rate: generalised seizures: 7/14 [50%], P = 0.03; absence seizures: 5/15 [33%], P
